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How long does it take for the Opioids listed in the Description to induce Analgesia when Administered via IV?

How long does it take for the Opioids listed in the Description to induce Analgesia when Administered via IV?


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How long does it take for the Opioids listed in the Description to induce Analgesia when Administered via IV? Now I don't mean how long it takes for euphoria to come on but analgesia.

The opioids I would like to know this information to include:

  • Buprenorphine
  • Butorphanol
  • Fentanyl
  • Hydromorphone
  • Methadone
  • Morphine
  • Oxycodone
  • Pentazocine
  • Pethidine (meperidine)
  • Sufentanil
  • Tramadol

These are 'peak' values when administered via IV, with the exception of oxycodone. There will be some variation person to person depending on their opioid tolerance and any concomitantly administered medications.

Buprenorphine: 60m

Butorphanol: 5m

Fentanyl: 5m

Hydromorphone: 30-90m

Methadone: 1-2h

Morphine: 20m

Oxycodone: Not administered intravenously

Pentazocine: 15m

Sufentanil: 3m

Tramadol: 2h


Medication-overuse headache

People who use acute pain-relief medicine more than two or three times a week or more than 10 days out of the month can set off a cycle called ‘medication-overuse headaches’ (MOH).

As each dose of medicine wears off, the pain comes back, leading them to take even more. This overuse causes your medicine to stop helping your pain and actually start causing headaches. MOH can occur with both over-the-counter and prescription pain-relief medicines. They can also occur whether you take them for headache or for another type of pain. Talk to your doctor if you think you have MOH.


Before taking this medicine

You should not be treated with this medicine if you are allergic to naloxone.

If possible before you receive a naloxone injection, tell your doctor if:

you have heart problems or

you are pregnant or breastfeeding.

Using naloxone while you are pregnant may cause opioid withdrawal effects in your unborn baby. However, having an opioid overdose can be fatal to both mother and baby. It is much more important to treat an overdose in the mother. You must get emergency medical help after using this medicine. Be sure all emergency medical caregivers know that you are pregnant.

If you use opioid medicine while you are pregnant, your baby could become dependent on the drug. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on opioids may need medical treatment for several weeks.

In an emergency, you may not be able to tell caregivers if you are pregnant or breastfeeding. Make sure any doctor caring for your pregnancy or your baby knows you received naloxone.


The Effects of Opioid Abuse on the Brain and Body

Opioids include drugs such as OxyContin and Vicodin that are mostly prescribed for the treatment of moderate to severe pain. They act by attaching to specific proteins called opioid receptors, which are found on nerve cells in the brain, spinal cord, gastrointestinal tract, and other organs in the body. When these drugs attach to their receptors, they reduce the perception of pain and can produce a sense of well-being however, they can also produce drowsiness, mental confusion, nausea, and constipation. [16] The effects of opioids are typically mediated by specific subtypes of opioid receptors (mu, delta, and kappa) that are activated by the body’s own (endogenous) opioid chemicals (endorphins, encephalins). With repeated administration of opioid drugs (prescription or heroin), the production of endogenous opioids is inhibited, which accounts in part for the discomfort that ensues when the drugs are discontinued (i.e., withdrawal). Adaptations of the opioid receptors’ signaling mechanism have also been shown to contribute to withdrawal symptoms.

Opioid medications can produce a sense of well-being and pleasure because these drugs affect brain regions involved in reward. People who abuse opioids may seek to intensify their experience by taking the drug in ways other than those prescribed. For example, extended-release oxycodone is designed to release slowly and steadily into the bloodstream after being taken orally in a pill this minimizes the euphoric effects. People who abuse pills may crush them to snort or inject which not only increases the euphoria but also increases the risk for serious medical complications, such as respiratory arrest, coma, and addiction. When people tamper with long-acting or extended-release medicines, which typically contain higher doses because they are intended for release over long periods, the results can be particularly dangerous, as all of the medicine can be released at one time. Tampering with extended release and using by nasal, smoked, or intravenous routes produces risk both from the higher dose and from the quicker onset.

Opioid pain relievers are sometimes diverted for nonmedical use by patients or their friends, or sold in the street. In 2012, over five percent of the U.S. population aged 12 years or older used opioid pain relievers non-medically. [17] The public health consequences of opioid pain reliever abuse are broad and disturbing. For example, abuse of prescription pain relievers by pregnant women can result in a number of problems in newborns, referred to as neonatal abstinence syndrome (NAS), which increased by almost 300 percent in the United States between 2000 and 2009. [18] This increase is driven in part by the high rate of opioid prescriptions being given to pregnant women. In the United States, an estimated 14.4 percent of pregnant women are prescribed an opioid during their pregnancy. [19]

Prescription opioid abuse is not only costly in economic terms (it has been estimated that the nonmedical use of opioid pain relievers costs insurance companies up to $72.5 billion annually in health-care costs [20] ) but may also be partly responsible for the steady upward trend in poisoning mortality. In 2010, there were 13,652 unintentional deaths from opioid pain reliever (82.8 percent of the 16,490 unintentional deaths from all prescription drugs), [21] and there was a five-fold increase in treatment admissions for prescription pain relievers between 2001 and 2011 (from 35,648 to 180,708, respectively). [22] In the same decade, there was a tripling of the prevalence of positive opioid tests among drivers who died within one hour of a crash. [23]

A property of opioid drugs is their tendency, when used repeatedly over time, to induce tolerance. Tolerance occurs when the person no longer responds to the drug as strongly as he or she did at first, thus necessitating a higher dose to achieve the same effect. The establishment of tolerance hinges on the ability of abused opioids (e.g., OxyContin, morphine) to desensitize the brain’s own natural opioid system, making it less responsive over time. [24] This tolerance contributes to the high risk of overdose during a relapse to opioid use after a period in recovery users who do not realize they may have lost their tolerance during a period of abstinence may initially take the high dosage that they previously had used before quitting, a dosage that produces an overdose in the person who no longer has tolerance. [25] Another contributing factor to the risk of opioid-related morbidity and mortality is the combined use of benzodiazepines (BZDs) and/or other CNS depressants, even if these agents are used appropriately. Thus, patients with chronic pain who use opioid analgesics along with BZDs (and/or alcohol) are at higher risk for overdose. Unfortunately, there are few available practice guidelines for the combined use of CNS depressants and opioid analgesics such cases warrant much closer scrutiny and monitoring. [26] Finally, it must be noted in this context that, although more men die from drug overdoses than women, the percentage increase in deaths seen since 1999 is greater among women: Deaths from opioid pain relievers increased five-fold between 1999 and 2010 for women versus 3.6 times among men. [27]


What is an epidural?

Epidural anesthesia is regional anesthesia that blocks pain in a particular region of the body. The goal of an epidural is to provide analgesia, or pain relief, rather than anesthesia, which leads to a total lack of feeling. Epidurals block the nerve impulses from the lower spinal segments. This results in decreased sensation in the lower half of the body.

Epidural medications fall into a class of drugs called local anesthetics, such as bupivacaine, chloroprocaine, or lidocaine. They are often delivered in combination with opioids or narcotics such as fentanyl and sufentanil in order to decrease the required dose of local anesthetic.

This produces pain relief with minimal effects. These medications may be used in combination with epinephrine, fentanyl, morphine, or clonidine to prolong the epidural’s effect or to stabilize the mother’s blood pressure.

How is an epidural given?

Intravenous (IV) fluids will be started before active labor begins and prior to the procedure of placing the epidural. You can expect to receive 1-2 liters of IV fluids throughout labor and delivery. An anesthesiologist (specialize in administering anesthesia), an obstetrician or nurse anesthetist will administer your epidural.

You will be asked to arch your back and remain still while lying on your left side or sitting up. This position is vital for preventing problems and increasing epidural effectiveness.

An antiseptic solution will be used to wipe the waistline area of your mid-back to minimize the chance of infection. A small area on your back will be injected with a local anesthetic to numb it. A needle is then inserted into the numbed area surrounding the spinal cord in the lower back.

After that, a small tube or catheter is threaded through the needle into the epidural space. The needle is then carefully removed, leaving the catheter in place to provide medication either through periodic injections or by continuous infusion. The catheter is taped to the back to prevent it from slipping out.

What are the different types?

There are two basic epidurals in use today. Hospitals and anesthesiologists will differ on the dosages and combinations of medication. You should ask your care providers at the hospital about their practices in this regard.

Regular Epidural

After the catheter is in place, a combination of narcotic and anesthesia is administered either by a pump or by periodic injections into the epidural space. A narcotic such as fentanyl or morphine is given to replace some of the higher doses of anesthetic, like bupivacaine, chloroprocaine, or lidocaine.

This helps reduce some of the adverse effects of the anesthesia. You will want to ask about your hospital’s policies about staying in bed and eating.

Combined Spinal-Epidural (CSE) or “Walking Epidural”

A spinal block is sometimes used in combination with an epidural during labor to provide immediate pain relief. A spinal block, like an epidural, involves an injection in the lower back. While you sit or lie on your side in bed, a small amount of medication is injected into the spinal fluid to numb the lower half of the body. It brings good relief from pain and starts working quickly, but it lasts only an hour or two and is usually given only once during labor. The epidural provides continued pain relief after the spinal block wears off.

What are the benefits of epidural anesthesia?

    • Allows you to rest if your labor is prolonged.
    • By reducing the discomfort of childbirth, some women have a more positive birth experience.
    • Normally, an epidural will allow you to stay alerted and remain an active participant in your birth.
    • When other types of coping mechanisms are no longer helping, an epidural can help you deal with exhaustion, irritability, and fatigue. An epidural can allow you to rest, relax, get focused, and give you the strength to move forward as an active participant in your birth experience.
    • The use of epidural anesthesia during childbirth is continually being refined, and much of its success depends on the skill with which it is administered.If you deliver by cesarean, an epidural anesthesia will allow you to stay awake and

    What are the risks of epidural anesthesia?

    • Epidurals may cause your blood pressure to suddenly drop. For this reason, your blood pressure will be routinely checked to help ensure adequate blood flow to your baby. If there is a sudden drop in blood pressure, you may need to be treated with IV fluids, medications, and oxygen.
    • You may experience a severe headache caused by leakage of spinal fluid. Less than 1% of women experience this side effect. If symptoms persist, a procedure called a “blood patch”, which is an injection of your blood into the epidural space can be performed to relieve a headache.
    • After your epidural is placed, you will need to alternate sides while lying in bed and have continuous monitoring for changes in fetal heart rate. Lying in one position can sometimes cause labor to slow down or stop.
    • You might experience the following side effects: shivering, a ringing of the ears, backache, soreness where the needle is inserted, nausea, or difficulty urinating.
    • You might find that your epidural makes pushing more difficult and additional medications or interventions may be needed, such as forceps or cesarean. Talk to your doctor when creating your birth plan about what interventions he or she generally uses in such cases.
    • For a few hours after the birth, the lower half of your body may feel numb. Numbness will require you to walk with assistance.
      In rare instances, permanent nerve damage may result in the area where the catheter was inserted.
    • Though research is somewhat ambiguous, most studies suggest that some babies will have trouble “latching on” causing breastfeeding difficulties. Other studies suggest that a baby might experience respiratory depression, fetal malpositioning, and an increase in fetal heart rate variability, thus increasing the need for forceps, vacuum, cesarean deliveries, and episiotomies.

    How Long Does an Epidural Last?

    Once the catheter is in place, the anaesthetist can set up an epidural pump. The pump feeds the epidural solution into the catheter continuously, providing pain relief for as long as needed.

    The type, amount and strength of the anaesthetic can be adjusted, as necessary. You might also be given the option of having control of the medication pump. This is called patient controlled analgesia. The amount of painkiller is still regulated, so you can’t accidentally overdose.

    You can have the dose lowered for second stage pushing, but it takes some time for the pain relief and numbness to wear off, so if this is important to you, discuss it with your care provider early on.

    Common Questions About Epidurals

    Does the placement of epidural anesthesia hurt?

    The answer depends on who you ask. Some women describe an epidural placement as creating a bit of discomfort in the area where the back was numbed, and a feeling of pressure as the small tube or catheter was placed.

    When will my epidural be placed?

    Typically epidurals are placed when the cervix is dilated to 4-5 centimeters and you are in true active labor.

    Can an epidural slow labor or lead to a cesarean delivery (C-section)?

    There is no credible evidence that it does either. When a woman needs a C-section, other factors usually are at play, including the size or position of the baby or slow progression of labor due to other issues. With an epidural, you might be able to feel contractions — they just won’t hurt — and you’ll be able to push effectively. There is some evidence that epidurals can speed the first stage of labor by allowing the mother to relax.

    How can an epidural affect my baby?

    As previously stated, research on the effects of epidurals on newborns is somewhat ambiguous, and many factors can affect the health of a newborn. How much of an effect these medications will have is difficult to predetermine and can vary based on dosage, the length of labor, and the characteristics of each individual baby.

    Since dosages and medications can vary, concrete information from research is currently unavailable. One possible side effect of an epidural with some babies is a struggle with “latching on” in breastfeeding. Another is that while in-utero, a baby might also become lethargic and have trouble getting into position for delivery.

    These medications have also been known to cause respiratory depression and decreased fetal heart rate in newborns. Though the medication might not harm these babies, they may have subtle effects on the newborn.

    How will I feel after the placement of an epidural?

    The nerves of the uterus should begin to numb within a few minutes after the initial dose. You will probably feel the entire numbing effect after 10-20 minutes. As the anesthetic dose begins to wear off, more doses will be given–usually every one to two hours.

    Depending on the type of epidural and dosage administered, you can be confined to your bed and not allowed to get up and move around.

    If labor continues for more than a few hours you will probably need urinary catheterization, because your abdomen will be numb, making urinating difficult. After your baby is born, the catheter is removed and the effects of the anesthesia will usually disappear within one or two hours.

    Some women report experiencing an uncomfortable burning sensation around the birth canal as the medication wears off.

    Will I be able to push?

    You might not be able to tell that you are having a contraction because of your epidural anesthesia. If you can not feel your contractions, then pushing may be difficult to control. For this reason, your baby might need additional help coming down the birth canal. This is usually done by the use of forceps.

    Does an epidural always work?

    For the most part, epidurals are effective in relieving pain during labor. Some women complain of being able to feel pain, or they feel that the drug worked better on one side of the body.

    When can an epidural NOT be used?

    An epidural may not be an option to relieve pain during labor if any of the following apply:


    Drug Dependence
    Naloxone hydrochloride injection should be administered cautiously to persons, including newborns of mothers, who are known or suspected to be physically dependent on opioids. In such cases an abrupt and complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

    The signs and symptoms of opioid withdrawal in a patient physically dependent on opioids may include, but are not limited to, the following: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In the neonate, opioid withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes.

    Repeat Administration
    The patient who has satisfactorily responded to Naloxone should be kept under continued surveillance and repeated doses of Naloxone should be administered, as necessary, since the duration of action of some opioids may exceed that of Naloxone.

    Respiratory Depression Due to Other Drugs
    Naloxone is not effective against respiratory depression due to non-opioid drugs and in the management of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete or require higher doses of Naloxone. If an incomplete response occurs, respirations should be mechanically assisted as clinically indicated.


    Commonly Used Drugs Charts

    Many drugs can alter a person’s thinking and judgment, and can lead to health risks, including addiction, drugged driving, infectious disease, and adverse effects on pregnancy. Information on commonly used drugs with the potential for misuse or addiction can be found here.

    On This Page:

    For information about treatment options for substance use disorders, see NIDA’s Treatment pages. For drug use trends, see our Trends and Statistics page. For the most up-to-date slang terms, please see Slang Terms and Code Words: A Reference for Law Enforcement Personnel (DEA, PDF, 1MB).

    People drink to socialize, celebrate, and relax. Alcohol often has a strong effect on people—and throughout history,people have struggled to understand and manage alcohol’s power. Why does alcohol cause people to act and feel differently? How much is too much? Why do some people become addicted while others do not? The National Institute on Alcohol Abuse and Alcoholism is researching the answers to these and many other questions about alcohol. Here’s what is known:

    Alcohol’s effects vary from person to person, depending on a variety of factors, including:

    • How much you drink
    • How often you drink
    • Your age
    • Your health status
    • Your family history

    While drinking alcohol is itself not necessarily a problem—drinking too much can cause a range of consequences, and increase your risk for a variety of problems.

    For more information on alcohol’s effects on the body, please see the National Institute on Alcohol Abuse and Alcoholism’s (NIAAA’s) related web page describing alcohol’s effects on the body. NIAAA also has some information about mixing alcohol with certain medicines.

    A tea made in the Amazon from a plant (Psychotria viridis) containing the hallucinogen DMT, along with another vine (Banisteriopsis caapi) that contains an MAO inhibitor preventing the natural breakdown of DMT in the digestive system, which enhances serotonergic activity. It was used historically in Amazonian religious and healing rituals. For more information, see the Hallucinogens and Dissociative Drugs Research Report.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Aya, Hoasca, Vine, Yagé No commercial uses Brewed as tea Swallowed as tea DMT is Schedule I**, but plants containing it are not controlled
    Possible Health Effects
    Short-term Strong hallucinations including altered visual and auditory perceptions increased heart rate and blood pressure nausea burning sensation in the stomach tingling sensations and increased skin sensitivity.
    Long-term Possible changes to the serotoninergic and immune systems, although more research is needed.
    Other Health-related Issues Unknown.
    In Combination with Alcohol Unknown.
    Withdrawal Symptoms Unknown.
    Treatment Options
    Medications It is not known whether ayahuasca is addictive. There are no FDA-approved medications to treat addiction to ayahuasca or other hallucinogens.
    Behavioral Therapies More research is needed to find out if ayahuasca is addictive and, if so, whether behavioral therapies are effective.

    Central Nervous System Depressants

    Medications that slow brain activity, which makes them useful for treating anxiety and sleep problems. For more information, see the Misuse of Prescription Drugs Research Report.

    Benzos, Downers, Poles, Tranks, Totem Z-Bars, Vs, Yellow/Blue Zs, Zannies

    A powerfully addictive stimulant drug made from the leaves of the coca plant native to South America. For more information, see the Cocaine Research Report.

    • Cognitive-behavioral therapy (CBT)
    • Contingency management, or motivational incentives, including vouchers
    • The Matrix Model
    • Community-based recovery groups, such as 12-Step programs
    • Mobile medical application: reSET ®

    Dimethyltriptamine (DMT) is a synthetic drug that produces intense but relatively short-lived hallucinogenic experiences it is also found naturally in some South American plants (see Ayahuasca). For more information, see the Hallucinogens and Dissociative Drugs Research Report.

    Businessman’s Special, DMT, Dimitri

    Gamma-hydroxybutyrate (GHB) is a depressant approved for use in the treatment of narcolepsy, a disorder that causes daytime "sleep attacks".

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    G, Gamma-oh, GEEB, Gina, Goop, Grievous Bodily Harm, Liquid Ecstasy, Liquid X, Scoop, Soap Gamma-hydroxybutyrate or sodium oxybate (Xyrem ® ) Colorless liquid, white powder Swallowed (often combined with alcohol or other beverages) I**
    Possible Health Effects
    Short-term Euphoria, drowsiness, nausea, vomiting, confusion, memory loss, unconsciousness, slowed heart rate and breathing, lower body temperature, seizures, coma, death.
    Long-term Unknown.
    Other Health-related Issues Sometimes used as a date rape drug.
    In Combination with Alcohol Nausea, problems with breathing, greatly increased depressant effects.
    Withdrawal Symptoms Insomnia, anxiety, tremors, sweating, increased heart rate and blood pressure, psychotic thoughts.
    Treatment Options
    Medications Benzodiazepines.
    Behavioral Therapies More research is needed to find out if behavioral therapies can be used to treat GHB addiction.

    Drugs that cause profound distortions in a person’s perceptions of reality, such as ketamine, LSD, mescaline (peyote), PCP, psilocybin, salvia, DMT, and ayahuasca. For more information, see the Hallucinogens and Dissociative Drugs Research Report.

    An opioid drug made from morphine, a natural substance extracted from the seed pod of various opium poppy plants. For more information, see the Heroin Research Report.

    With OTC nighttime cold medicine: Cheese

    • Methadone
    • Buprenorphine
    • Naltrexone (short- and long-acting forms)
    • Contingency management, or motivational incentives
    • 12-Step facilitation therapy
    • Mobile medical application: reSET-O™ used in conjunction with treatment that includes buprenorphine and contingency management

    Solvents, aerosols, and gases found in household products such as spray paints, markers, glues, and cleaning fluids also prescription nitrites. For more information, see the Inhalants Research Report.

    Spravato TM (esketamine), prescribed for treatment resistant depression used under strict medical supervision

    Pronounced "cot," a shrub (Catha edulis) found in East Africa and southern Arabia contains the psychoactive chemicals cathinone and cathine. People from African and Arabian regions (up to an estimated 20 million worldwide) have used khat for centuries as part of cultural tradition and for its stimulant-like effects.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Catha, Chat, Kat, Oat No commercial uses Fresh or dried leaves Chewed, brewed as tea Cathinone is a Schedule I drug**, making khat use illegal, but the khat plant is not controlled
    Possible Health Effects
    Short-term Euphoria, increased alertness and arousal, increased blood pressure and heart rate, depression, paranoia, headaches, loss of appetite, insomnia, fine tremors, loss of short-term memory.
    Long-term Gastrointestinal disorders such as constipation, ulcers, and stomach inflammation and increased risk of heart attack.
    Other Health-related Issues In rare cases associated with heavy use: psychotic reactions such as fear, anxiety, grandiose delusions (fantastical beliefs that one has superior qualities such as fame, power, and wealth), hallucinations, and paranoia.
    In Combination with Alcohol Unknown.
    Withdrawal Symptoms Depression, nightmares, low blood pressure, and lack of energy.
    Treatment Options
    Medications It is not known whether khat is addictive. There are no FDA-approved medications to treat addiction to khat.
    Behavioral Therapies More research is needed to find out if khat is addictive and, if so, whether behavioral therapies are effective.

    A tropical deciduous tree (Mitragyna speciosa) native to Southeast Asia, with leaves that contain many compounds, including mitragynine, a psychotropic (mind-altering) opioid. Kratom is consumed for mood-lifting effects and pain relief and as an aphrodisiac. For more information, see the Kratom DrugFacts.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Herbal Speedball, Biak-biak, Ketum, Kahuam, Thang, Thom None Fresh or dried leaves, powder, liquid, gum Chewed (whole leaves) eaten (mixed in food or brewed as tea) occasionally smoked Not scheduled
    Possible Health Effects
    Short-term Nausea, dizziness, itching, sweating, dry mouth, constipation, increased urination, loss of appetite.
    Low doses: increased energy, sociability, alertness.
    High doses: sedation, euphoria, decreased pain.
    Long-term Anorexia, weight loss, insomnia, skin darkening, dry mouth, frequent urination, constipation. Hallucinations with long-term use at high doses in some users.
    Other Health-related Issues Unknown.
    In Combination with Alcohol Unknown.
    Withdrawal Symptoms Muscle aches, insomnia, hostility, aggression, emotional changes, runny nose, jerky movements.
    Treatment Options
    Medications No clinical trials have been conducted on medications for kratom addiction.
    Behavioral Therapies More research is needed to find out if behavioral therapies can be used to treat addiction to kratom.

    A hallucinogen manufactured from lysergic acid, which is found in ergot, a fungus that grows on rye and other grains. LSD is an abbreviation of the scientific name lysergic acid diethylamide. For more information, see the Hallucinogens and Dissociative Drugs Research Report.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Acid, Blotter, Boomers, Cid, Golden Dragon, Looney Tunes, Lucy Mae, Microdots, Tabs, Yellow Sunshine No commercial uses Tablet capsule clear liquid small, decorated squares of absorbent paper that liquid has been added to Swallowed, absorbed through mouth tissues (paper squares) I**
    Possible Health Effects
    Short-term Rapid emotional swings distortion of a person’s ability to recognize reality, think rationally, or communicate with others raised blood pressure, heart rate, body temperature dizziness loss of appetite tremors enlarged pupils.
    Long-term Frightening flashbacks (called Hallucinogen Persisting Perception Disorder [HPPD]) ongoing visual disturbances, disorganized thinking, paranoia, and mood swings.
    Other Health-related Issues Unknown.
    In Combination with Alcohol Unknown.
    Withdrawal Symptoms Unknown.
    Treatment Options
    Medications There are no FDA-approved medications to treat addiction to LSD or other hallucinogens.
    Behavioral Therapies More research is needed to find out if behavioral therapies can be used to treat addiction to hallucinogens.

    Marijuana is made from the hemp plant, Cannabis sativa. The main psychoactive (mind-altering) chemical in marijuana is delta-9-tetrahydrocannabinol, or THC. For more information, see the Marijuana Research Report.

    Hashish: Boom, Gangster, Hash, Hemp

    Concentrates: Budder, Crumble, Shatter, Wax

    • Cognitive-behavioral therapy (CBT)
    • Contingency management, or motivational incentives
    • Motivational Enhancement Therapy (MET)
    • Behavioral treatments geared to adolescents
    • Mobile medical application: reSET ®

    A synthetic, psychoactive drug that has similarities to both the stimulant amphetamine and the hallucinogen mescaline. MDMA is an abbreviation of the scientific name 3,4-methylenedioxy-methamphetamine. For more information, see the MDMA (Ecstasy) Abuse Research Report.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Adam, E, X, XTC, Beans, Candy, E-bomb, Thizz, Love Drug, Molly, Rolls, Skittles, Sweets, Vitamin E or X. No commercial uses is being researched as therapy for Post Traumatic Stress Disorder (PTSD) under strict medical supervision. Colorful tablets with imprinted logos, capsules, powder, liquid Swallowed, snorted I**
    Possible Health Effects
    Short-term Lowered inhibition enhanced sensory perception increased heart rate and blood pressure muscle tension nausea faintness chills or sweating sharp rise in body temperature leading to kidney failure or death.
    Long-term Long-lasting confusion, depression, problems with attention, memory, and sleep increased anxiety, impulsiveness less interest in sex.
    Other Health-related Issues Unknown.
    In Combination with Alcohol MDMA decreases some of alcohol’s effects. Alcohol can increase plasma concentrations of MDMA, which may increase the risk of neurotoxic effects.
    Withdrawal Symptoms Fatigue, loss of appetite, depression, trouble concentrating.
    Treatment Options
    Medications There is conflicting evidence about whether MDMA is addictive. There are no FDA-approved medications to treat MDMA addiction.
    Behavioral Therapies More research is needed to find out if behavioral therapies can be used to treat MDMA addiction.

    A hallucinogen found in disk-shaped “buttons” in the crown of several cacti, including peyote. For more information, see the Hallucinogens DrugFacts.

    An extremely addictive stimulant amphetamine drug. For more information, see the Methamphetamine Research Report.

    • Cognitive-behavioral therapy (CBT)
    • Contingency management, or motivational incentives
    • The Matrix Model
    • 12-Step facilitation therapy
    • Mobile medical application: reSET ®

    Over-the-Counter Medicines--Dextromethorphan (DXM)

    Psychoactive when taken in higher-than-recommended amounts. For more information, see the Over the Counter Medicines DrugFacts.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Robo, Robotripping, Skittles, Triple C Various (many brand names include “DM”) Syrup, capsule Swallowed Not scheduled
    Possible Health Effects
    Short-term Cough relief euphoria slurred speech increased heart rate and blood pressure dizziness nausea vomiting.
    Long-term Unknown.
    Other Health-related Issues Breathing problems, seizures, and increased heart rate may occur from other ingredients in cough/cold medicines.
    In Combination with Alcohol Unknown.
    Withdrawal Symptoms Unknown.
    Treatment Options
    Medications There are no FDA-approved medications to treat addiction to dextromethorphan.
    Behavioral Therapies More research is needed to find out if behavioral therapies can be used to treat addiction to dextromethorphan.

    An anti-diarrheal that can cause euphoria when taken in higher-than-recommended doses. For more information, see the Over the Counter Medicines DrugFacts.

    • The same behavioral therapies that have helped treat addiction to heroin may be used to treat addiction to loperamide.
    • Contingency management, or motivational incentives

    Low doses: slight increase in breathing rate increased blood pressure and heart rate shallow breathing face redness and sweating numbness of the hands or feet problems with movement.

    With soft drinks/candy: Lean, Sizzurp, Purple Drank

    Pregnancy: Miscarriage, low birth weight, neonatal abstinence syndrome.

    Older adults: higher risk of accidental misuse because many older adults have multiple prescriptions, increasing the risk of drug-drug interactions, and breakdown of drugs slows with age also, many older adults are treated with prescription medications for pain.

    Risk of HIV, hepatitis, and other infectious diseases from shared needles.

    Medications that increase alertness, attention, energy, blood pressure, heart rate, and breathing rate. For more information, see the Misuse of Prescription Drugs Research Report.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Addys, Bennies, Beans, Black Beauties, Crosses, Hearts, Ivy League Drug, Pep Pills, Speed, Uppers Amphetamine (Adderall ® ) Tablet, capsule Swallowed, snorted, smoked, injected II**
    Diet Coke, JIF, Kiddie Coke, MPH, R-Ball, R-Pop, Skippy, Study Buddies , The Smart Drug, Vitamin R Methylphenidate (Concerta ® , Ritalin ® ) Liquid, tablet, chewable tablet, capsule Swallowed, snorted, smoked, injected, chewed II**
    Possible Health Effects
    Short-term Increased alertness, attention, energy increased blood pressure and heart rate narrowed blood vessels increased blood sugar opened-up breathing passages.

    • Behavioral therapies that have helped treat addiction to cocaine or methamphetamine may be useful in treating prescription stimulant addiction.
    • Mobile medical application: reSET ®

    A hallucinogen in certain types of mushrooms that grow in parts of South America, Mexico, and the United States. For more information, see the Hallucinogens and Dissociative Drugs Research Report.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Little Smoke, Magic Mushrooms, Purple Passion, Sacred Mush, Sewage Fruit, Shrooms, Zoomers No commercial uses being researched as therapy for treatment-resistant depression under strict medical supervision. Fresh or dried mushrooms with long, slender stems topped by caps with dark gills Swallowed (eaten, brewed as tea, or added to other foods) I**
    Possible Health Effects
    Short-term Hallucinations, altered perception of time, inability to tell fantasy from reality, panic, muscle relaxation or weakness, problems with movement, enlarged pupils, nausea, vomiting, drowsiness.
    Long-term Risk of flashbacks and memory problems.
    Other Health-related Issues Risk of poisoning if a poisonous mushroom is accidentally used.
    In Combination with Alcohol May decrease the perceived effects of alcohol.
    Withdrawal Symptoms Unknown.
    Treatment Options
    Medications It is not known whether psilocybin is addictive. There are no FDA-approved medications to treat addiction to psilocybin or other hallucinogens.
    Behavioral Therapies More research is needed to find out if psilocybin is addictive and whether behavioral therapies can be used to treat addiction to this or other hallucinogens.

    A benzodiazepine chemically similar to prescription sedatives such as Valium® and Xanax® that may be misused for its psychotropic effects. Rohypnol has been used to commit sexual assaults because of its strong sedation effects. In these cases, offenders may dissolve the drug in a person’s drink without their knowledge.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Circles, Date Rape Drug, Forget-Me Pill, La Rocha, Mind Eraser, Pingus, R2, Rib, Variations of: Roaches, Roapies, Rochas Dos, Roofies, Rope, Rophies, Rowie, Ruffies Flunitrazepam, Rohypnol ® Tablet Swallowed (as a pill or as dissolved in a drink), snorted IV** - Rohypnol® is not approved for medical use in the United States it is available as a prescription sleep aid in other countries
    Possible Health Effects
    Short-term Drowsiness, sedation, sleep amnesia, blackout decreased anxiety muscle relaxation, impaired reaction time and motor coordination impaired mental functioning and judgment confusion aggression excitability slurred speech headache slowed breathing and heart rate.
    Long-term Unknown.
    Other Health-related Issues Unknown.
    In Combination with Alcohol Severe sedation, unconsciousness, and slowed heart rate and breathing, which can lead to death.
    Withdrawal Symptoms Headache muscle pain extreme anxiety, tension, restlessness, confusion, irritability numbness and tingling of hands or feet hallucinations, delirium, convulsions, seizures, or shock.
    Treatment Options
    Medications There are no FDA-approved medications to treat addiction to Rohypnol® or other prescription sedatives.
    Behavioral Therapies More research is needed to find out if behavioral therapies can be used to treat addiction to Rohypnol® or other prescription sedatives.

    A dissociative drug that is an herb in the mint family native to southern Mexico. Dissociative drugs are hallucinogens that cause the user to feel detached from reality. For more information, see the Hallucinogens and Dissociative Drugs Research Report.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Chia seeds, Diviner’s Sage, Magic Mint, Sally-D, Ska Pastora Sold legally in most states as Salvia divinorum Fresh or dried leaves Smoked, chewed, or brewed as tea Not Scheduled
    (but labeled drug of concern by DEA and illegal in some states)
    Possible Health Effects
    Short-term Short-lived but intense hallucinations altered visual perception, mood, body sensations mood swings, feelings of detachment from one’s body sweating.
    Long-term Unknown.
    Other Health-related Issues Unknown.
    In Combination with Alcohol Unknown.
    Withdrawal Symptoms Unknown.
    Treatment Options
    Medications It is not known whether salvia is addictive. There are no FDA-approved medications to treat addiction to salvia or other dissociative drugs.
    Behavioral Therapies More research is needed to find out if salvia is addictive, but behavioral therapies can be used to treat addiction to dissociative drugs.

    Man-made substances used to treat conditions caused by low levels of steroid hormones in the body and misused to enhance athletic and sexual performance and physical appearance. For more information, see the Steroids and Other Appearance and Performance Enhancing Drugs (APEDs) Research Report.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Gear, Gym Candy, Juice, Pumpers, Roids, Stacking Nandrolone (Oxandrin ® ), oxandrolone (Anadrol ®), oxymetholone (Anadrol-50 ® ), testosterone cypionate (Depo-testosterone ® )
    Tablet, capsule, liquid drops, gel, cream, patch, injectable solution Injected, swallowed, applied to skin III**
    Possible Health Effects
    Short-term Builds muscles, improved athletic performance. Acne, fluid retention (especially in the hands and feet), oily skin, yellowing of the skin, infection.
    Long-term Kidney damage or failure liver damage high blood pressure, enlarged heart, or changes in cholesterol leading to increased risk of stroke or heart attack, even in young people aggression extreme mood swings anger ("roid rage") extreme irritability delusions impaired judgment.
    Other Health-related Issues Males: shrunken testicles, lowered sperm count, infertility, baldness, development of breasts.

    Females: facial hair, male-pattern baldness, enlargement of the clitoris, deepened voice.

    Adolescents: stunted growth.

    A wide variety of herbal mixtures containing man-made cannabinoid chemicals related to THC in marijuana but often much stronger and more dangerous. Sometimes misleadingly called “synthetic marijuana” and marketed as a “natural,” "safe," legal alternative to marijuana. For more information, see the Synthetic Cannabinoids DrugFacts.

    Common Names Commercial Names Common Forms Common Ways Taken DEA Schedule
    Black Mamba, Bliss Fake Weed, Fire, Genie, K-2, Moon Rocks, Solar Flare, Skunk, Smacked, Spice, Yucatan, Zohai No commercial uses, but new formulations are sold under various names to attract young adults. Many formulations have been outlawed. Dried, shredded plant material that looks like potpourri and is sometimes sold as “incense” Smoked, swallowed (brewed as tea) I**
    Possible Health Effects
    Short-term Increased heart rate vomiting agitation confusion hallucinations, anxiety, paranoia increased blood pressure.
    Long-term Unknown.
    Other Health-related Issues Use of synthetic cannabinoids has led to an increase in emergency room visits in certain areas.
    In Combination with Alcohol Unknown.
    Withdrawal Symptoms Headaches, anxiety, depression, irritability.
    Treatment Options
    Medications There are no FDA-approved medications to treat K2/Spice addiction.
    Behavioral Therapies More research is needed to find out if behavioral therapies can be used to treat synthetic cannabinoid addiction.

    Synthetic Cathinones (Bath Salts)

    An emerging family of drugs containing one or more synthetic chemicals related to cathinone, a stimulant found naturally in the khat plant. Examples of such chemicals include mephedrone, methylone, and 3,4-methylenedioxypyrovalerone (MDPV). For more information, see the Synthetic Cathinones DrugFacts.

    • Cognitive-behavioral therapy (CBT)
    • Contingency management, or motivational incentives
    • Motivational Enhancement Therapy (MET)
    • Behavioral treatments geared to teens

    Tobacco is a plant grown for its leaves, which are dried and fermented before use. Tobacco contains nicotine, an addictive chemical. Nicotine is sometimes extracted from the plant and is used in vaping devices. For more information, see the Tobacco, Nicotine and E-Cigarettes Research Report.

    Butts, Cancer sticks, Ciggys, Cigs, Coffin nails, Smokes, Stogies, Stokes

    Cigar hollowed out with marijuana added: Blunt

    Tobacco products: Use while pregnant can lead to miscarriage, low birth weight, stillbirth, learning and behavior problems.

    • Bupropion (Zyban ® )
    • Varenicline (Chantix ® )
    • Nicotine replacement (gum, patch, lozenge)
    • Cognitive-behavioral therapy (CBT)
    • Self-help materials
    • Mail, phone, and internet quitting resources

    ** Drugs are classified into five distinct categories or schedules "depending upon the drug’s acceptable medical use and the drug’s abuse or dependency potential." More information and the most up-to-date scheduling information can be found on the Drug Enforcement Administration’s website.


    VIVITROL isone dose a month

    After intramuscular injection, the naltrexone plasma concentration time profile is characterized by a transient initial peak, which occurs approximately 2 hours after injection, followed by a second peak observed approximately 2-3 days later. Beginning approximately 14 days after dosing, concentrations slowly decline, with measurable levels for greater than 1 month. 1

    MEAN NALTREXONE CONCENTRATION 1-3

    Data for oral naltrexone beyond Day 5 have been extrapolated from a study of normal healthy volunteers (n=14) given oral naltrexone 50 mg daily for 5 days.

    Plasma concentrations do not necessarily correlate with clinical efficacy.

    Dosage and Administration 1 :

    VIVITROL must be prepared and administered by a healthcare provider.

    Prior to initiating VIVITROL, an opioid-free duration of a minimum of 7–10 days is recommended for patients, to avoid precipitation of withdrawal that may be severe enough to require hospitalization.

    VIVITROL is available in one dose, 380 mg, delivered intramuscularly every 4 weeks or once a month by a healthcare provider.

    • VIVITROL must not be administered intravenously or subcutaneously
    • Inadvertent subcutaneous injection of VIVITROL may increase the likelihood of severe injection site reactions
    • Alternate buttocks for each subsequent injection
    • The needles provided in the carton are customized needles. VIVITROL must not be injected using any other needle. Proper needle from the carton should be selected based on body habitus
    • Administer with caution in patients with moderate to severe renal impairment, thrombocytopenia, or any other coagulation disorder
    • If a patient misses a dose, he/she should be instructed to receive the next dose as soon as possible
    • Patients reinitiating treatment with VIVITROL should be opioid-free at the time of dose administration
    • Patients should be alerted that they may be more sensitive to opioids, even at lower doses
    • See additional dosage and administration information in the VIVITROL Full Prescribing Information

    VIVITROL is not right for everyone. There are significant risks from VIVITROL treatment, including risk of opioid overdose, injection site reactions and sudden opioid withdrawal.
    See Important Safety Information below. Discuss all benefits and risks with your patients. See Prescribing Information. Review Medication Guide with your patients.

    Fulfillment for specialty medications can be complex

    Do your patients need help paying for VIVITROL?
    Help patients find you. Become a healthcare provider listed on vivitrol.com

    REQUEST A REPRESENTATIVE

    Request a visit from a VIVITROL representative
    to learn more about how VIVITROL may help
    your patients with opioid dependence and
    alcohol dependence.

    LEARN ABOUT THE VIVITROL ® CO-PAY SAVINGS PROGRAM

    Learn how the VIVITROL ® Co-pay Savings Program may assist eligible* patients with out-of-pocket expenses for their VIVITROL prescriptions.

    IMPORTANT SAFETY INFORMATION FOR VIVITROL ® (NALTREXONE FOR EXTENDED-RELEASE INJECTABLE SUSPENSION)

    INDICATIONS

    VIVITROL is indicated for:

    • Treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with VIVITROL. Patients should not be actively drinking at the time of initial VIVITROL administration.
    • Prevention of relapse to opioid dependence, following opioid detoxification.
    • VIVITROL should be part of a comprehensive management program that includes psychosocial support.

    CONTRAINDICATIONS

    VIVITROL is contraindicated in patients:

    • Receiving opioid analgesics
    • With current physiologic opioid dependence
    • In acute opioid withdrawal
    • Who have failed the naloxone challenge test or have a positive urine screen for opioids
    • Who have exhibited hypersensitivity to naltrexone, polylactide-co-glycolide (PLG), carboxymethylcellulose, or any other components of the diluent

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    Vulnerability to Opioid Overdose:

    • After opioid detoxification, patients are likely to have a reduced tolerance to opioids. VIVITROL blocks the effects of exogenous opioids for approximately 28 days after administration. As the blockade wanes and eventually dissipates completely, use of previously tolerated doses of opioids could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.).
    • Cases of opioid overdose with fatal outcomes have been reported in patients who used opioids at the end of a dosing interval, after missing a scheduled dose, or after discontinuing treatment. Patients and caregivers should be told of this increased sensitivity to opioids and the risk of overdose. Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver, at the initial VIVITROL injection and with each subsequent injection. Strongly consider prescribing naloxone for the emergency treatment of opioid overdose.
    • Although VIVITROL is a potent antagonist with a prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable. The plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids.
    • Any attempt by a patient to overcome the VIVITROL blockade by taking opioids may lead to fatal overdose. Patients should be told of the serious consequences of trying to overcome the opioid blockade.

    Injection Site Reactions:

    • VIVITROL must be prepared and administered by a healthcare provider.
    • VIVITROL injections may be followed by pain, tenderness, induration, swelling, erythema, bruising, or pruritus however, in some cases injection site reactions may be very severe.
    • In the clinical trials, one patient developed an area of induration that continued to enlarge after 4 weeks, with subsequent development of necrotic tissue that required surgical excision.
    • Injection site reactions not improving may require prompt medical attention, including, in some cases, surgical intervention.
    • Inadvertent subcutaneous/adipose layer injection of VIVITROL may increase the likelihood of severe injection site reactions.
    • Select proper needle size for patient body habitus, and use only the needles provided in the carton.
    • Patients should be informed that any concerning injection site reactions should be brought to the attention of their healthcare provider.

    Precipitation of Opioid Withdrawal:

    • When withdrawal is precipitated abruptly by administration of an opioid antagonist to an opioid-dependent patient, the resulting withdrawal syndrome can be severe. Some cases of withdrawal symptoms have been severe enough to require hospitalization, and in some cases, management in the ICU.
    • To prevent occurrence of precipitated withdrawal, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting VIVITROL treatment:
      • An opioid-free interval of a minimum of 7–10 days is recommended for patients previously dependent on short-acting opioids.
      • Patients transitioning from buprenorphine or methadone may be vulnerable to precipitated withdrawal for as long as two weeks.

      Hepatotoxicity:

      • Cases of hepatitis and clinically significant liver dysfunction have been observed in association with VIVITROL. Warn patients of the risk of hepatic injury advise them to seek help if experiencing symptoms of acute hepatitis. Discontinue use of VIVITROL in patients who exhibit acute hepatitis symptoms.

      Depression and Suicidality:

      • Alcohol- and opioid-dependent patients taking VIVITROL should be monitored for depression or suicidal thoughts. Alert families and caregivers to monitor and report the emergence of symptoms of depression or suicidality.

      When Reversal of VIVITROL Blockade Is Required for Pain Management:

      • For VIVITROL patients in emergency situations, suggestions for pain management include regional analgesia or use of non-opioid analgesics. If opioid therapy is required to reverse the VIVITROL blockade, patients should be closely monitored by trained personnel in a setting staffed and equipped for CPR.

      Eosinophilic Pneumonia:

      • Patients who develop dyspnea and hypoxemia should seek medical attention immediately. Consider the possibility of eosinophilic pneumonia in patients who do not respond to antibiotics.

      Hypersensitivity Reactions including Anaphylaxis:

      • Cases of urticaria, angioedema, and anaphylaxis have been observed with the use of VIVITROL.
      • Patients should be warned of the risk of hypersensitivity reactions, including anaphylaxis.
      • In the event of a hypersensitivity reaction, patients should be advised to seek immediate medical attention in a healthcare setting prepared to treat anaphylaxis. The patient should not receive any further treatment with VIVITROL.

      Intramuscular Injections:

      • As with any intramuscular injection, VIVITROL should be administered with caution to patients with thrombocytopenia or any coagulation disorder.

      Alcohol Withdrawal:

      Interference with Laboratory Tests

      • VIVITROL may be cross-reactive with certain immunoassay methods for the detection of drugs of abuse (specifically opioids) in urine.
      • For further information, reference to the specific immunoassay instructions is recommended.

      ADVERSE REACTIONS

      • The adverse events seen most frequently in association with VIVITROL therapy for alcohol dependence (ie, those occurring in &ge5% and at least twice as frequently with VIVITROL than placebo) include nausea, vomiting, injection site reactions (including induration, pruritus, nodules, and swelling), arthralgia, arthritis, or joint stiffness, muscle cramps, dizziness or syncope, somnolence or sedation, anorexia, decreased appetite or other appetite disorders.
      • The adverse events seen most frequently in association with VIVITROL in opioid-dependent patients (ie, those occurring in &ge2% and at least twice as frequently with VIVITROL than placebo) were hepatic enzyme abnormalities, injection site pain, nasopharyngitis, insomnia, and toothache.

      You are encouraged to report side effects to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

      See Prescribing Information and Medication Guide.

      1. VIVITROL [prescribing information]. Waltham, MA: Alkermes, Inc rev March 2021.
      2. Dunbar JL, Turncliff RZ, Dong Q, Silverman BL, Ehrich EW, Lasseter KC. Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone. Alcohol Clin Exp Res. 200630(3):480-490.
      3. Dean RL. The preclinical development of Medisorb ® naltrexone, a once a month long-acting injection, for the treatment of alcohol dependence. Front Biosci. 200510:643-655.

      *Terms and Conditions

      Eligibility for Alkermes-Sponsored Co-pay Savings. This offer is only available to patients 18 years or older, with a prescription consistent with the Prescribing Information and the patient is not enrolled in, or covered by, any local, state, federal or other government program that pays for any portion of medication costs, including but not limited to Medicare, including Medicare Part D or Medicare Advantage plans Medicaid, including Medicaid Managed Care and Alternative Benefit Plans under the Affordable Care Act Medigap VA DOD TRICARE or a residential correctional program.
      Additional Terms of Use: This offer is not conditioned on any past, present, or future purchase, including refills. Alkermes reserves the right to rescind, revoke, or amend this offer, program eligibility, and requirements at any time without notice. This offer is limited to one per patient, may not be used with any other offer, is not transferable and may not be sold, purchased or traded, or offered for sale, purchase or trade. Void where prohibited by law. Program Administrator or its designee will have the right upon reasonable prior written notice, during normal business hours, and subject to applicable law, to audit compliance with this program.

      As of December 8, 2015, VIVITROL ® (naltrexone for extended-release injectable suspension) has new Prescribing Information (12/2015). The Dosage and Administration, Section 2.4 Directions for Use has been updated. When administering VIVITROL, please refer to Section 2.4 Directions for Use in the VIVITROL Prescribing Information that is provided in the carton you are administering.

      As of December 8, 2015, VIVITROL ® (naltrexone for extended-release injectable suspension) has new Prescribing Information (12/2015). The Dosage and Administration, Section 2.4 Directions for Use has been updated. When administering VIVITROL, please refer to Section 2.4 Directions for Use in the VIVITROL Prescribing Information that is provided in the carton you are administering.


      EQUIPMENT FOR SPINAL ANESTHESIA

      Maintaining Asepsis

      No single intervention guarantees asepsis. Therefore, a multiprong approach is advisable.
      In the past, most institutions had reusable trays for spinal anesthesia. These trays required preparation by anesthesiologists or anesthesia personnel to ensure that bacterial and chemical contamination would not occur. Currently, commercially prepared, disposable spinal trays are available and are in use by most institutions. These trays are portable, sterile, and easy to use. Figure 9 shows the contents of a standard, commercially prepared spinal anesthetic tray.

      The ideal skin preparation solution should be bactericidal and have a quick onset and long duration. Chlorhexidine is superior to povidone iodine in all these respects. In addition, the ideal agent should not be neurotoxic. Unfortunately, bactericidal agents are neurotoxic. It is therefore prudent to use the lowest effective concentration and allow the preparation to dry. Although subject to debate, 0.5% chlorhexidine in alcohol 70% is currently recommended by some groups. Contamination of equipment with skin preparation can theoretically lead to the introduction of neurotoxic substances into neural tissue. Of more concern is accidental neuraxial injection of antiseptic solution, possibly from antiseptic solution and local anesthetic being placed in adjacent pots. Therefore, after skin preparation, unused antiseptic should be discarded before commencement of the procedure (and intrathecal drugs should be drawn directly from sterile ampules). Tinted antiseptic solutions may decrease the likelihood of drug error and allow easy identification of missed skin during application.
      Proving a benefit of individual infection control measures is difficult due to the rarity of infectious complications. Past evidence has been contradictory. For example, it has been suggested that shedding of skin scales from mask “wiggling” may occur, increasing bacterial contamination. Yet, in 1995 there were calls for routine face mask use after it was unambiguously proven, using polymerase chain reaction (PCR) fingerprinting, that a case of Streptococcus salivarius meningitis originated in the throat of the doctor who had performed a lumbar puncture.

      It is our strong belief that face mask wearing should be mandatory when performing spinal anesthesia. A 2006 American Society of Regional Anesthesia and Pain Medicine (ASRA) practice advisory recommended mask wearing in addition to removing jewelry, thorough hand washing, and sterile surgical gloves for all regional anesthesia techniques.
      Major components of an aseptic technique also included a surgical hat and sterile draping. Other international professional bodies have similar guidelines.
      Prophylactic antibiotics are unnecessary for spinal anesthesia. If, as it happens, antibiotic prophylaxis is required for the prevention of surgical site infection, it may be prudent to administer antibiotics before insertion of a spinal needle.
      The reader is referred to Infection Control in Regional Anesthesia for more information.

      Resuscitation and Monitoring

      Resuscitation equipment must be available whenever a spinal anesthetic is performed. This includes equipment and medication required to secure an airway, provide ventilation, and support cardiac function. All patients receiving spinal anesthesia should have an intravenous line.
      The patient must be monitored during the placement of the spinal anesthetic with a pulse oximeter, blood pressure cuff, and ECG. Fetal monitoring should be used in the case of a pregnant patient. Noninvasive blood pressure should be measured at 1-minute intervals initially, as hypotension may be sudden.
      Shivering and body habitus may make noninvasive blood pressure measurement difficult. Consideration should be given to invasive blood pressure monitoring if the patient has significant cardiovascular disease.

      Needles

      Needles of different diameters and shapes have been developed for spinal anesthesia. The ones currently used have a close-fitting, removable stylet, which prevents skin and adipose tissue from plugging the needle and possibly entering the subarachnoid space. Figure 10 shows the different types of needles used along with the type of point at the end of the needle.
      The pencil-point needles (Sprotte and Whitacre) have a rounded, noncutting bevel with a solid tip. The opening is located on the side of the needle 2–4 mm proximal to the tip of the needle. The needles with cutting bevels include the Quincke and Pitkin needles. The Quincke needle has a sharp point with a medium-length cutting needle, and the Pitkin has a sharp point and short bevel with cutting edges. Finally, the Greene spinal needle has a rounded point and rounded noncutting bevel. If a continuous spinal catheter is to be placed, a Tuohy needle can be used to find the subarachnoid space before placement of the catheter.
      Pencil-point needles provide a better tactile sensation of the layers of ligament encountered but require more force to insert than bevel-tip needles. The bevel of the needle should be directed longitudinally to decrease the incidence of PDPH.

      Small-gauge needles and needles with rounded, noncutting bevels also decrease the incidence of PDPH but are more easily deflected than larger-gauge needles. The reader is referred to Ultrastructural Anatomy of the Spinal Meninges and Related Structures and Postdural Puncture Headache.

      NYSORA Tips

      • Pencil-point needles provide a better tactile sensation of the layers of ligament encountered but require more force to insert than bevel-tip needles.
      • The use of introducers help preventing the passage of epidermic contaminants to the CSF.

      Introducers have been designed to assist with the placement of spinal needles into the subarachnoid space due to the difficulty in directing needles of small bore through the tissues. Introducers also serve to prevent contamination of the CSF with small pieces of epidermis, which could lead to the formation of dermoid spinal cord tumors. The introducer is placed into the interspinous ligament in the intended direction of the spinal needle, and the spinal needle is then placed through the introducer.


      Background

      Spinal administration of opioids has been demonstrated to be effective in the management of patients with chronic malignant pain. It has also been used in the treatment of chronic non-malignant pain such as reflex sympathetic dystrophy (RSD), also known as complex regional pain syndrome (CRPS). In some patients who have failed physical therapy and medical treatment, hospitalization (4 to 6 days) for continuous epidural narcotic analgesia, with or without local anesthetics, may be necessary to break the pain cycle and prevent worsening of RSD symptoms. This route of administration allows maximum narcotic effect in the dorsal horn with very low blood levels, thus minimizing toxicity.

      On the other hand, there is a lack of scientific evidence on the effectiveness of intrapleural analgesia for treatment of CRPS with chronic pain involving the thoracic dermatomes.

      Ketamine hydrochloride, an agent used for general anesthesia, has local anesthetic effects as well as N-methyl-D-aspartate (NMDA) receptor antagonist action. During the last decade it has been shown that low, sub-anesthetic doses of ketamine may produce effective analgesia, especially when combined with opioids (Bell et al, 2002). Moreover, it has been suggested that ketamine may have potential in treating CRPS as co-analgesics when used in combination with opioids (Hewitt, 2000 Singh and Patel, 2001). However, there is insufficient evidence to support the use of intravenous ketamine in the treatment of CRPS/RSD. Hord and Oaklander (2003) noted that some common treatments (e.g., local anesthetic blockade of sympathetic ganglia) are not supported by the aggregate of published studies.

      In an evidence-based review on the use of ketamine in the management of chronic pain, Hocking and Cousins (2003) concluded that the evidence for efficacy of ketamine for treatment of chronic pain is moderate to weak and that further controlled studies are needed. Additionally, Kingery (1997) noted that intravenous ketamine is not a realistic option for treatment of chronic neuropathic pain due to intolerable side-effects associated with long-term infusion.

      The effectiveness of systemic lidocaine in the treatment of chronic pain (e.g., intractable neuropathic pain) has not been established. In a randomized controlled study (n = 22), Taskaynatan and colleagues (2004) examined the effect of intravenous regional anesthesia (Bier block) with methylprednisolone and lidocaine in CRPS type I. These investigators concluded that Bier block with methylprednisolone and lidocaine in CRPS type I does not provide long-term benefit in CRPS, and its short-term benefit is not superior to placebo. Furthermore, in a review on chronic neuropathic pain (Harden 2005), intravenous lidocaine is not listed as a treatment option. In addition, guidelines from the International Research Foundation for RSD/CRPS (2003) do not state that intravenous lidocaine is indicated for CRPS.

      In a Cochrane systematic review, Cepeda et al (2005) reviewed the evidence supporting the use of intravenous regional anesthesia (Bier blocks) for CRPS. The investigators identified 2 small randomized double-blind cross-over studies that evaluated 23 subjects. The combined effect of the 2 trials produced a relative risk (RR) to achieve at least 50 % of pain relief 30 mins to 2 hrs after the sympathetic blockade of 1.17 (95 % confidence interval [CI]: 0.80 to1.72). The investigators stated that it was not possible to determine the effect of sympathetic blockade on long-term pain relief because the 2 randomized controlled trials (RCTs) evaluated different outcomes. Cepeda et al (2005) concluded that this systematic review revealed the scarcity of published evidence to support the use of local anesthetic sympathetic blockade as the "gold standard" treatment for CRPS. The 2 randomized studies that met inclusion criteria had very small sample sizes therefore, no conclusion concerning the effectiveness of this procedure could be drawn. The investigators concluded that there is a need to conduct RCTs to address the value of sympathetic blockade with local anesthetic for the treatment of CRPS.

      In a review on the management of patients with RSD/CRPS type I, Berthelot (2006) stated that mirror visual feedback was introduced recently for the rehabilitation of these patients. This approach entails the use of visual input from a moving, unaffected limb to re-establish the pain-free relationship between sensory feedback and motor execution. However, the author concluded that the effectiveness of mirror visual feedback in treating RSD/CRPS type I needs to be assessed in RCTs.

      Rothgangel and associates (2011) evaluated the clinical aspects of mirror therapy (MT) interventions after stroke, phantom limb pain and CRPS. A systematic literature search of the Cochrane Database of controlled trials, PubMed/MEDLINE, CINAHL, EMBASE, PsycINFO, PEDro, RehabTrials and Rehadat, was made by 2 investigators independently. No restrictions were made regarding study design and type or localization of stroke, CRPS and amputation. Only studies that had MT given as a long-term treatment were included. Two authors independently assessed studies for eligibility and risk of bias by using the Amsterdam-Maastricht Consensus List. A total of 10 randomized trials, 7 patient series and 4 single-case studies were included. The studies were heterogeneous regarding design, size, conditions studied and outcome measures. Methodological quality varied only a few studies were of high quality. Important clinical aspects, such as assessment of possible side effects, were only insufficiently addressed. For stroke, there is a moderate quality of evidence that MT as an additional intervention improves recovery of arm function, and a low quality of evidence regarding lower limb function and pain after stroke. The authors stated that the quality of evidence in patients with CRPS and phantom limb pain is also low. Firm conclusions could not be drawn. Little is known about which patients are likely to benefit most from MT, and how MT should preferably be applied. Future studies with clear descriptions of intervention protocols should focus on standardized outcome measures and systematically register adverse effects.

      In a pilot study, Kiefer and colleagues (2008a) investigated the effectiveness of subanesthetic isomeric S(+)-ketamine in refractory CRPS patients. Four refractory CRPS patients received continuous S(+)-ketamine-infusions, gradually titrated (50 mg/day to 500 mg/day) over a 10-day period. Pain intensities (average, peak, and least pain) and side effects were rated on visual analog scale (VAS), during a 4-day baseline, over 10 treatment days, and 2 days following treatment. Quantitative sensory testing (QST: thermo-, mechanical detection, and pain thresholds) was analyzed at baseline and following treatment. Subanesthetic S(+)-ketamine showed no reduction of pain and effected no change in thermo- and mechanical detection or pain thresholds. This procedure caused no relevant side effects. The lack of therapeutic response in the first 4 patients led to termination of this pilot study. The authors concluded that S(+)-ketamine can be gradually titrated to large doses (500 mg/day) without clinically relevant side effects. There was no pain relief or change in QST measurements in this series of long-standing severe CRPS patients.

      In an open label phase II study, Kiefer et al (2008b) examined the effectiveness of ketamine in anesthetic dosage in refractory CRPS patients who had failed available standard therapies. A total of 20 American Society of Anesthesiologists (ASA) I-III patients suffering from refractory CRPS received ketamine in anesthetic dosage over 5 days. Outcome criteria were pain relief, effect on the movement disorder, quality of life, and ability to work at baseline and up to 6 months following treatment. Significant pain relief was observed at 1, 3, and 6 months following treatment (93.5 +/- 11.1 %, 89.4 +/- 17.0 %, 79.3 +/- 25.3 % p < 0.001). Complete remission from CRPS was observed at 1 month in all patients, at 3 months in 17, and at 6 months in 16 patients. If relapse occurred, significant pain relief was still attained at 3 and 6 months (59.0 +/- 14.7 %, p < 0.004 50.2 +/- 10.6 %, p < 0.002). Quality of life, the associated movement disorder, and the ability to work significantly improved in the majority of patients at 3 and 6 months. The authors concluded that these findings suggest benefit in pain reduction, associated CRPS symptoms, improved quality of life and ability to work following anesthetic ketamine in previously refractory CRPS patients. However, they stated that a RCT will be needed to prove its effectiveness.

      Goldberg et al (2005) reported on the effectiveness of low-dose outpatient ketamine infusion for the treatment of CRPS diagnosed by International Association for the Study of Pain criteria in patients who have failed conservative treatment. Patients diagnosed with CRPS by a single neurologist were assigned to receive a 10-day outpatient infusion of ketamine supervised by an anesthesiologist/pain management specialist. The infusion was administered in a short procedure unit after each patient had been instructed on how to complete a pain questionnaire. Monitoring consisted of continuous ECG, pulse oximetry, and non-invasive blood pressure every 15 mins. Patients made journal entries each day prior to the infusion of 40 to 80 mg of ketamine. Subjects were also asked to rate their pain intensity using a verbal analog scale of 0 to 10 and the affective component using a verbal scale of 0 to 4. There was a significant reduction in pain intensity from initiation of infusion (day 1) to the 10th day, with a significant reduction in the percentage of patients experiencing pain by day 10 as well as a reduction in the level of their "worst" pain. The nadirs of pain were lower by day 10 with a significant reduction in the incidence of "punishing pain". Moreover, there was a significant improvement in the ability to initiate movement by the 10th day. The authors concluded that a 4-hr ketamine infusion escalated from 40 to 80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation. They also stated that although pain data showed some variability, the results are encouraging and point to the need for additional studies.

      Webster and Walker (2006) examined the safety and effectiveness of prolonged low-dose, continuous intravenous (IV) or subcutaneous ketamine infusions in non-cancer outpatients. A total of 13 outpatients with neuropathic pain were administered low-dose IV or subcutaneous ketamine infusions for up to 8 weeks under close supervision by home health care personnel. Using the 10-point VAS, 11 of 13 patients (85 %) reported a decrease in pain from the start of infusion treatment to the end. Side effects were minimal and not severe enough to deter treatment. Prolonged analgesic doses of ketamine infusions were safe for the small sample studied. The authors concluded that these findings demonstrate that ketamine may provide a reasonable alternative treatment for non-responsive neuropathic pain in ambulatory outpatients. Moreover, the authors stated that additional studies should follow to ascertain optimal dose and duration for specific pain disorders and to minimize side effects. They also noted that questions regarding which patients would be most susceptible to this type of therapy and when treatment should be instituted remain unanswered.

      Kiefer and associates (2007) described the treatment of an intractable CRPS-I patient with anesthetic doses of ketamine supplemented with midazolam. The patient presented with a rapidly progressing contiguous spread of CRPS from a severe ligamentous wrist injury. Standard pharmacological and interventional therapy successively failed to halt the spread of CRPS from the wrist to the entire right arm. Her pain was unmanageable with all standard therapy. As a last treatment option, the patient was transferred to the intensive care unit and treated on a compassionate care basis with anesthetic doses of ketamine in gradually increasing (3 to 5 mg/kg/h) doses in conjunction with midazolam over a period of 5 days. On the 2nd day of the ketamine and midazolam infusion, edema, and discoloration began to resolve and increased spontaneous movement was noted. On day 6, symptoms completely resolved and infusions were tapered. The patient emerged from anesthesia completely free of pain and associated CRPS signs and symptoms. The patient has maintained this complete remission from CRPS for 8 years now. The authors concluded that in a patient with severe spreading and refractory CRPS, a complete and long-term remission from CRPS has been obtained utilizing ketamine and midazolam in anesthetic doses. This intensive care procedure has very serious risks but no severe complications occurred. The psychiatric side effects of ketamine were successfully managed with the concomitant use of midazolam and resolved within 1 month of treatment. The authors stated that large RCTs are needed to confirm the finding of this single case.

      In a case report, Shirani et al (2008) described the effect of ketamine infusion in the treatment of severe refractory CRPS I. The patient was initially diagnosed with CRPS I in her right upper extremity. Over the next 6 years, CRPS was consecutively diagnosed in her thoracic region, left upper extremity, and both lower extremities. The severity of her pain, combined with the extensive areas afflicted by CRPS, caused traumatic emotional problems for this patient. Conventional treatments failed to provide long-term relief from pain. The patient was then given several infusions of IV ketamine. After the 3rd infusion, the edema, discoloration, and temperature of the affected areas normalized. The patient became completely pain-free. At 1-year follow-up, the patient reported that she has not experienced any pain since the last ketamine infusion. The authors concluded that treatment with IV ketamine appeared to be effective in completely resolving intractable pain caused by severe refractory CRPS I. Moreover, they stated that more research on this treatment is needed to better define its effectiveness in CRPS.

      Sigtermans et al (2009) evaluated if ketamine improves pain in CRPS-1 patients. A total of 60 patients (48 females) with severe pain participated in a double-blind randomized placebo-controlled parallel-group trial. Patients were given a 4.2-day intravenous infusion of low-dose ketamine (n = 30) or placebo (n = 30) using an individualized step-wise tailoring of dosage based on effect (pain relief) and side effects (nausea/vomiting/psychomimetic effects). The primary outcome of the study was the pain score (numerical rating score: 0 to 10) during the 12-week study period. The median (range) disease duration of the patients was 7.4 (0.1 to 31.9) years. At the end of infusion, the ketamine dose was 22.2 +/- 2.0 mg/hr/70 kg body weight. Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo (p < 0.001). The lowest pain score was at the end of week 1: ketamine 2.68 +/- 0.51, placebo 5.45 +/- 0.48. In week 12, significance in pain relief between groups was lost (p = 0.07). Treatment did not cause functional improvement. Patients receiving ketamine more often experienced mild-to-moderate psychomimetic side effects during drug infusion (76 % versus 18 %, p < 0.001). The authors concluded that in a population of mostly chronic CRPS-1 patients with severe pain at baseline, a multiple day ketamine infusion resulted in significant pain relief without functional improvement. However, it is important to note that the significance in pain relief between groups was lost in week 12.

      Henson and Bruehl (2010) stated that although the pathophysiology of CRPS is unclear, it appears to reflect multiple interacting mechanisms. In addition to altered autonomic function, a role for inflammatory mechanisms and altered somatosensory and motor function in the brain is increasingly suggested. Several possible risk factors for development of CRPS, including genetic factors, have been identified. Few treatments have been proven effective for CRPS in well-designed clinical trials. However, recent work suggests that bisphosphonates may be useful in CRPS management and that the NMDA receptor antagonist ketamine significantly reduces CRPS pain when administered topically or intravenously at subanesthetic dosages. Extended use of ketamine at anesthetic dosages ("ketamine coma") remains a controversial and unproven treatment for CRPS. Spinal cord stimulation may be effective for reducing pain in approximately 2/3 of CRPS patients not responding to other treatments, but its efficacy appears to diminish over time.

      Collins and colleagues (2010) performed a meta-analysis evaluating the effects of (individual) NMDA receptor antagonists on neuropathic pain, and the response (sensitivity) of individual neuropathic pain disorders to NMDA receptor antagonist therapy. PubMed (including MEDLINE), EMBASE and CENTRAL were searched up to October 26, 2009 for RCTs on neuropathic pain. The methodological quality of the included trials was independently assessed by 2 authors using the Delphi list. Fixed or random effects model were used to calculate the summary effect size using Hedges' "g" (unbiased estimator). The outcome of measurements was the reduction of spontaneous pain. A total of 28 studies were included, meeting the inclusion criteria. Summary effect sizes were calculated for subgroups of studies evaluating ketamine IV in CRPS, oral memantine in post-herpetic neuralgia and, respectively, ketamine IV, and oral memantine in post-amputation pain. Treatment with ketamine significantly reduced pain in post-amputation pain (pooled summary effect size: -1.18 (95 % CI: -1.98 to 0.37, p = 0.004). No significant effect on pain reduction could be established for ketamine IV in CRPS (-0.65 [95 % CI: -1.47 to 0.16], p = 0.11) oral memantine in post-herpetic neuralgia (0.03 [95 % CI: -0.51 to 0.56], p = 0.92) and for oral memantine in post-amputation pain (0.38 [95 % CI: -0.21 to 0.98], p = 0.21). The authors concluded that based on this systematic review, no conclusions can yet be made about the efficacy of NMDA receptor antagonists on neuropathic pain. They stated that additional RCTs in homogenous groups of pain patients are needed to explore the therapeutic potential of NMDA receptor antagonists in neuropathic pain.

      Sabia et al (2011) noted that historically, CRPS was poorly defined, which meant that scientists and clinicians faced much uncertainty in the study, diagnosis, and treatment of the syndrome. The problem could be attributed to a non-specific diagnostic criteria, unknown pathophysiologic causes, and limited treatment options. The 2 forms of CRPS still are painful, debilitating disorders whose sufferers carry heavy emotional burdens. Current research has shown that CRPS-1 and CRPS-2 are distinctive processes, and the presence or absence of a partial nerve lesion distinguishes them apart. Ketamine has been the focus of various studies involving the treatment of CRPS however, currently, there is incomplete data from evidence-based studies. The question as to why ketamine is effective in controlling the symptoms of a subset of patients with CRPS and not others remains to be answered. A possible explanation to this phenomenon is pharmacogenetic differences that may exist in different patient populations.

      Azari and colleagues (2012) reviewed published literature for evidence of the safety and effectiveness of ketamine in the treatment of CRPS. PubMed and the Cochrane Controlled Trials Register were searched (final search May 26, 2011) using the MeSH terms "ketamine", "complex regional pain syndrome", "analgesia" and "pain" in the English literature. The manuscript bibliographies were then reviewed to identify additional relevant papers. Observational trials were evaluated using the Agency for Healthcare Research and Quality criteria randomized trials were evaluated using the methodological assessment of RCTs. The search methodology yielded 3 randomized, placebo-controlled trials, 7 observational studies and 9 case studies/reports. In aggregate, the data available reveal ketamine as a promising treatment for CRPS. The optimum dose, route and timing of administration remain to be determined. The authors concluded that RCTs are needed to establish the safety and effectiveness of ketamine and to determine its long-term benefit in CRPS.

      MacDaniel (2003) reported 3 cases in which electroconvulsive therapy (ECT) for depression led to the relief of co-morbid CRPS as well as depression. In one of the cases, concomitant fibromyalgia was not relieved during 2 separate series of ECT. Wolanin et al (2007) reported a case of CRPS in a patient who also suffered from medically refractory depression. She was treated with ECT for her depression and subsequently was relieved of all her CRPS symptoms. The subject, a 42-year old female, underwent a series of 12 standard bi-temporal ECT for medically refractory depression. Physical examination and QST were performed before and after the patient's treatment with ECT. This standard treatment procedure for refractory depression completely resolved the patient's depressive symptoms. In addition, the patient's CRPS symptoms were also reversed. Physical examination as well as QST carried out before and after the ECT treatment correlated with her CRPS symptom improvement. The authors concluded that ECT was effective in the treatment of severe refractory CRPS in this patient. The findings of these studies need to be validated by well-designed studies.

      Kemler and associates (2008) assessed the effectiveness of spinal cord stimulation (SCS) in reducing pain due to CRPS-I at the 5-year follow-up. The authors performed a randomized trial in a 2:1 ratio in which 36 patients with CRPS-I were allocated to receive SCS and physical therapy (PT) and 18 patients to receive PT alone. Twenty-four patients who received SCS pluse PT also underwent placement of a permanent spinal cord stimulator after successful test stimulation the remaining 12 patients did not receive a permanent stimulator. These researchers evaluated pain intensity, global perceived effect, treatment satisfaction, and health-related quality of life. Patients were examined before randomization, before implantation, and every year until 5 years thereafter. A total of 10 patients were excluded from the final analysis. At 5 years post-treatment, SCS plus PT produced results similar to those following PT for pain relief and all other measured variables. In a sub-group analysis, the results with regard to global perceived effect (p = 0.02) and pain relief (p = 0.06) in 20 patients with an implant exceeded those in 13 patients who received PT.

      1. percutaneous radiofrequency (RF) thermal lumbar sympathectomy and
      2. lumbar sympathetic neurolysis.

      In a prospective, RCT, Fischer et al (2008) evaluated the effectiveness of occlusal splint (OS) therapy on self-reported measures of pain in patients with chronic CRPS as compared with a non-treatment group. A total of 20 patients with CRPS were randomly assigned to either the OS or control group. Patients in the OS group were asked to use the OS at night-time and for 3 hrs during day-time for a total of 7 weeks the control group had no stomatognathic intervention. The primary outcome was self-reported assessment of CRPS-related pain on numerical rating scales. Secondary outcome measures were the temporomandibular index (TMI), and the Short Form 36 Health Survey (SF-36). All patients had TMD signs and symptoms, but OS had no effect on CRPS-related pain on the numerical rating scale (p > 0.100). The changes in the TMI scores over time were 16.6 % +/- 24.6 % (improvement) in the OS group and -21.3 % +/- 25.9 % (impairment) in the control group that was significant (p = 0.004). There were no differences in the changes of SF-36 scores between groups (p = 0.636). The authors concluded that the use of OS for 7 weeks has no impact on CRPS-related pain, but improved signs and symptoms of TMD pain. They stated that future studies should include an active control group and evaluate if long-term changes in measures of oral health impact general health in CRPS-related pain.

      van Rijn and colleagues (2009) stated that dystonia in CRPS responds poorly to treatment. Intrathecal baclofen (ITB) may improve this type of dystonia, but information on its efficacy and safety is limited. A single-blind, placebo-run-in, dose-escalation study was carried out in 42 CRPS patients to evaluate whether dystonia responds to IT. Thirty-six of the 38 patients, who met the responder criteria received a pump for continuous ITB administration, and were followed-up for 12 months to assess long-term efficacy and safety (open-label study). Primary outcome measures were global dystonia severity (both studies) and dystonia-related functional limitations (open-label study). The dose-escalation study showed a dose-effect of baclofen on dystonia severity in 31 patients in doses up to 450 microg/day. One patient did not respond to treatment in the dose-escalation study and 3 patients dropped out. Thirty-six patients entered the open-label study. Intention-to-treat analysis revealed a substantial improvement in patient and assessor-rated dystonia scores, pain, disability and quality-of-life (QOL) at 12 months. The response in the dose-escalation study did not predict the response to ITB in the open-label study. Eighty-nine adverse events occurred in 26 patients and were related to baclofen (n = 19), pump/catheter system defects (n = 52), or could not be specified (n = 18). The pump was explanted in 6 patients during the follow-up phase. Dystonia, pain, disability and QOL all improved on ITB and remained efficacious over a period of 1 year. However, ITB is associated with a high complication rate in this patient group, and methods to improve patient selection and catheter-pump integrity are warranted.

      Tran et al (2010) summarized the evidence derived from RCTs pertaining to the treatment of CRPS. Using the Medline (January 1950 to April 2009) and Embase (January 1980 to April 2009) databases, the following medical subject headings (MeSH) were searched: "complex regional pain syndrome", "reflex sympathetic dystrophy", and "causalgia" as well as the key words "algodystrophy", "Sudeck's atrophy", "shoulder hand syndrome", "neurodystrophy", "neuroalgodystrophy", "reflex neuromuscular dystrophy", and "posttraumatic dystrophy". Results were limited to RCTs conducted on human subjects, written in English, published in peer-reviewed journals, and pertinent to treatment. The search criteria yielded 41 RCTs with a mean of 31.7 subjects per study. Blinded assessment and sample size justification were provided in 70.7 % and 19.5 % of RCTs, respectively. Only bisphosphonates appear to offer clear benefits for patients with CRPS. Improvement has been reported with dimethyl sulfoxide, epidural clonidine, ITB, motor imagery programs, spinal cord stimulation, and steroids, but further trials are required. The available evidence does not support the use of calcitonin, vasodilators, or sympatholytic and neuromodulative intravenous regional blockade. Clear benefits have not been reported with stellate/lumbar sympathetic blocks, mannitol, gabapentin, and physical/occupational therapy. The authors concluded that published RCTs can only provide limited evidence to formulate recommendations for treatment of CRPS. In this review, no study was excluded based on factors such as sample size justification, statistical power, blinding, definition of intervention allocation, or clinical outcomes. Thus, evidence derived from "weaker" trials may be over-emphasized. These researchers stated that further well-designed RCTs are warranted.

      In a randomized, double-blind, placebo-controlled cross-over study, Goebel et al (2010) assessed the effectiveness of intravenous immunoglobulin (IVIG) in patients with longstanding CRPS. Persons who had pain intensity greater than 4 on an 11-point (0 to 10) numerical rating scale and had CRPS for 6 to 30 months that was refractory to standard treatment were enrolled in this trial. Subjects received IVIG, 0.5 g/kg, and normal saline in separate treatments, divided by a washout period of at least 28 days. The primary outcome was pain intensity 6 to 19 days after the initial treatment and the cross-over treatment. A total of 13 eligible participants were randomly assigned 12 completed the trial. The average pain intensity was 1.55 units lower after IVIG treatment than after saline (95 % CI: 1.29 to 1.82 p < 0.001). In 3 patients, pain intensity after IVIG was less than after saline by 50 % or more. No serious adverse reactions were reported. The authors concluded that low-dose IVIG can reduce pain in refractory CRPS. The drawbacks of this trial were small sample size, recruitment bias, and chance variation could have influenced results and their interpretation. The authors stated that more studies are needed to determine the best immunoglobulin dose, the duration of effect, and when repeated treatments are needed.

      In an editorial that accompanied the afore-mentioned study, Birklein and Sommer (2010) noted that "a less obvious but critical limitation is the missing placebo response, which raises doubts about the adequacy of blinding. The observed response to IVIG (20 % to 30 % pain reduction from baseline) is in the range that one would expect for the placebo response. Another concern relates to the definition of "refractory to standard treatment" as a criterion for patient eligibility. Study participants had not tried certain treatments that have been shown to have some effectiveness in randomized, controlled trials, such as motor or sensory learning, steroids, bisphosphonates, and sympathetic blocks . A closer look at the individual treatment responses in Goebel and colleagues' study shows another reason that future trials should use "enriched" designs. Although 3 of 13 patients had very positive responses, the remaining 10 patients had no or only a transient response. If one could identify patients likely to respond, the efficacy of treatment and the cost-effectiveness ratio might be greatly improved. Only then might IVIG offer what we have long looked for: a safe, effective, easy-to-adhere-to, and scientifically validated treatment for CRPS".

      In a pilot study, Breuer and colleagues (2008) examined the safety and effectiveness of ibandronate (a highly potent bisphosphonate) for the treatment of CRPS. A total of 10 patients received 6-mg ibandronate infusions on each of 3 days. The infusions were preceded by a 2-week baseline period, and followed by a 4-week follow-up period. One subject dropped out after the first infusion because of a decreased glomerular filtration rate. Aside from transitory flu-like symptoms characteristic of bisphosphonate treatments, the drug was well-tolerated. Significant post-intervention improvements were observed in average and worst pain ratings the neuropathic pain qualities of "unpleasant", "sensitive", "deep", "intense", "surface", "hot","cold", "sharp", and "dull" and hyperalgesia and allodynia. Subjects with hand CRPS improved significantly more than those with foot CRPS in average and worst pain, as well as in the following neuropathic pain qualities: "dull", "intense", "deep" and "time". The authors concluded that these findings justify a randomized, double-blind, placebo-controlled trial of ibandronate that should perhaps be limited to patients with hand CRPS.

      Brunner et al (2009) performed a systematic review of all RCTs to evaluate the benefit of biphosphonates in the treatment of CRPS-1 patients with bone loss. These investigators selected RCTs comparing biphosphonates with placebo, with the goal of improving pain, function and quality of life in patients with CRPS-1. Two reviewers independently assessed trial eligibility and quality, and extracted data. Where data were incomplete or unclear, conflicts were resolved with discussion and/or trial authors were contacted for further details. They calculated the study size weighted pooled mean reduction of pain intensity (measured with a VAS). Four trials of moderate quality fulfilled the inclusion criteria. In respect to function and quality of life there was a trend in favor of biphosphonates but differences in outcome assessment impeded pooling of results. Two trials provided sufficient data to pool pain outcomes. Biphosphonates reduced pain intensity by 22.4 and 21.6 mm on a VAS after 4 and 12 weeks of follow-up. Data on adverse effects were scarce. The authors concluded that the very limited data reviewed showed that bisphosphonates have the potential to reduce pain associated with bone loss in patients with CRPS -1. However, at present there is insufficient evidence to recommend their use in practice.

      In a randomized, double-blind, placebo-controlled, parallel-group trial, Munts et al (2010) examined the safety and effectiveness of a single intrathecal administration of 60 mg methylprednisolone (ITM) in chronic patients with CRPS. The primary outcome measure was change in pain (pain intensity numeric rating scale range of 0 to 10) after 6 weeks. With 21 subjects per group, the study had a 90 % power to detect a clinically relevant difference (greater than or equal to 2 points). After 21 patients (10 on ITM) were included, the trial was stopped prematurely after the interim analysis had shown that ITM had no effect on pain (difference in mean pain intensity numeric rating scale at 6 weeks 0.3, 95 % CI: -0.7 to 1.3) or any other outcome measure. These researchers did not find any difference in treatment-emergent adverse events between the ITM and placebo group. The authors concluded that a single bolus administration of ITM is not effective in chronic CRPS patients, which may indicate that spinal immune activation does not play an important role in this phase of the syndrome.

      In a pilot study, Safarpour et al (2010) investigated the effectiveness and tolerability of botulinum toxin A (BoNT-A) in allodynia of patients with CRPS. A total of 14 patients were studied -- 8 patients were participants of a randomized, prospective, double-blind, placebo-controlled protocol 6 patients were studied prospectively in an open-label protocol. Patients were rated at baseline and at 3 weeks and 2 months after BoNT-A administration. Ratings included brief pain inventory, McGill pain questionnaire, clinical pain impact questionnaire, quantitative skin sensory test, sleep satisfaction scale, and patient global satisfaction scale. BoNT-A was injected intradermally and subcutaneously, 5 units/site into the allodynic area (total dose 40 to 200 units). None of the patients with allodynia showed a significant response after treatment. The treatment was painful and poorly-tolerated. The authors concluded that intrademal and subcutaneous administration of BoNT-A into the allodynic skin of the patients with CRPS failed to improve pain and was poorly-tolerated.

      Basford et al (2003) assessed the physiological effects of linearly polarized red and near-infrared (IR) light and quantitated its benefits in people with upper extremity pain due to CRPS I (RSD). This was a 2-part study. In the 1st phase, 6 adults (aged 18 to 60 years) with normal neurological examinations underwent transcutaneous irradiation of their right stellate ganglion with linearly polarized 0.6 to 1.6 microm light (0.92 W, 88.3 J) 2nd phase consisted of a double-blinded evaluation of active and placebo radiation in 12 subjects (aged 18 to 72 years) of which 6 had upper extremity CRPS I and 6 served as "normal" controls. Skin temperature, heart rate (HR), sudomotor function, and vasomotor tone were monitored before, during, and for 30 mins following irradiation. Analgesic and sensory effects were assessed over the same period as well as 1 and 2 weeks later. Three of 6 subjects with CRPS I and no control subjects experienced a sensation of warmth following active irradiation (p = 0.025). Two of the CRPS I subjects reported a greater than 50 % pain reduction. However, 4 noted minimal or no change and improvement did not reach statistical significance for the group as a whole. No statistically significant changes in autonomic function were noted. There were no adverse consequences. The authors concluded that irradiation was well-tolerated. There is a suggestion in this small study that treatment is beneficial and that its benefits are not dependent on changes in sympathetic tone. They stated that further evaluation is warranted.

      In a systematic review, Dirckx and colleagues (2012) described the current empirical evidence for the effectiveness of administering the most commonly used immunomodulating medication (i.e., bisphosphonates, glucocorticoids, immunoglobulins, thalidomide, and tumor necrosis factor-α antagonists) in CRPS patients. PubMed was searched for original articles that investigated CRPS and the use of one of the afore-mentioned immunomodulating agents. The search yielded 39 relevant articles: from these, information on study design, sample size, duration of disease, type and route of medication, primary outcome measures, and results was examined. The authors concluded that theoretically, the use of immunomodulating medication could counteract the ongoing inflammation and might be an important step in improving a disabled hand or foot, leading to further recovery. However, they stated that more high-quality intervention studies are needed.

      Chronic pain generally refers to persistent, non-acute, sometimes disabling pain in the extremities or other areas of the body. The pain can be associated with a known cause such as a major or minor injury, or it can be a symptom of a painful chronic condition or be of unknown etiology. Chronic pain syndrome is a diagnosis of exclusion. It is usually considered ongoing pain lasting longer than 6 months, with some using three months as a minimum criteria. It is associated with diffuse arthralgia and myalgia without signs of joint swelling, muscle weakness, weight loss or fever. Post traumatic pain syndrome is one of the historical terms used to describe excess pain with or without sympathetic dysfunction.

      The spinal accessory nerve is the eleventh cranial nerve. It emerges from the skull and receives an extra root (or accessory) from the upper part of the spinal cord. This nerve supplies the sternocleidomastoid and trapezius muscles. The sternocleidomastoid muscle is in the front of the neck and turns the head while the trapezius muscle moves the scapula, turns the head to the opposite side, and helps pull the head back. Neurolysis is the destruction of nerves to promote analgesia or pain relief.

      Diazgranados et al (2010) conducted a randomized, placebo-controlled, double-blind, cross-over, add-on study to determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression. The main outcome variable was measured using the Montgomery-Asberg Depression Rating Scale primary efficacy measure scores. The results illustrated that within 40 minutes depressive symptoms significantly improved in subjects receiving ketamine compared with placebo, with a drug difference effect size being largest at day 2 71 % of subjects responded to ketamine and 6 % responded to placebo.

      Aan et al (2012) conducted a systematic review of all available published data on the antidepressant effects of ketamine, including all recently completed, ongoing, and planned studies. They reported that as of the publication of their report, 163 patients, primarily with treatment-resistant depression, had participated in case studies, open-label investigations, or controlled trials. All reported trials used a within-subject, cross-over design with inactive placebo controls. Response rates for the clinical trials and open-label investigations ranged from 25 % to 85 % 24 hours post-treatment. Seventy-two hours post-treatment response rates in the afore-mentioned studies was 14 % to 70 %. The authors concluded that further research of ketamine for individuals with severe mood disorders is warranted, but they did not recommend administration outside of the hospital setting due to the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks.

      Martin et al (2013) described, for the first time, the use of multiple peripheral nerve catheters to treat CRPS type I in a 10-year old girl who had failed multi-modal pharmacologic regimens. At separate times, a peripheral nerve catheter was placed to treat CRPS of the distal left lower extremity as well as the right upper extremity. The goal of this therapy was to relieve pain and thereby allow the re-initiation of intensive PT. A continuous infusion of 0.1 % ropivacaine was infused via the catheters for approximately 60 hours. The patient was subsequently able to participate in PT as well as activities of daily living with improved eating, sleeping, and mood. The authors concluded that although many therapeutic modalities have been tried in CRPS type I, given the debilitating nature of the disorder and the variable response to therapy, new and alternative therapeutic interventions, such as continuous peripheral nerve catheters, are needed. The findings of this single case study need to be validated by well-designed studies.

      An UpToDate review on “Prevention and management of complex regional pain syndrome in adults” (Abdi, 2014) states that “Experimental approaches -- Several different approaches have been of interest for the treatment of longstanding or refractory CRPS, including intravenous ketamine, intravenous magnesium, tadalafil, mirror therapy, and intravenous immunoglobulin”.

      The Colorado Division of Workers' Compensation’s medical treatment guidelines on “Complex regional pain syndrome/reflex sympathetic dystrophy” (2011) noted that “Sympathetic injections are generally accepted, well-established procedures. They include stellate ganglion blocks and lumbar sympathetic blocks. Unfortunately, there are no high quality randomized controlled trials in this area."

      The Washington State Department of Labor and Industries’ guidelines on “Work-related complex regional pain syndrome (CRPS): Diagnosis and treatment” (2011) stated that “Sympathetic blocks have long been a standard treatment for CRPS and can be useful for a subset of cases. Stellate ganglion blocks (cervical sympathetic blocks) and lumbar sympathetic blocks are widely used in the management of upper and lower extremity CRPS. There is limited evidence to confirm effectiveness. An initial trial of up to three sympathetic blocks should be considered when the condition fails to improve with conservative treatment, including analgesia and physical therapy."

      Hey et al (2014) identified through case study the presentation and possible pathophysiological cause of complex regional pain syndrome and its preferential response to stellate ganglion blockade. Complex regional pain syndrome can occur in an extremity after minor injury, fracture, surgery, peripheral nerve insult or spontaneously and is characterized by spontaneous pain, changes in skin temperature and color, edema, and motor disturbances. Pathophysiology is likely to involve peripheral and central components and neurological and inflammatory elements. There is no consistent approach to treatment with a wide variety of specialists involved. Diagnosis can be difficult, with over-diagnosis resulting from undue emphasis placed upon pain disproportionate to an inciting event despite the absence of other symptoms or under-diagnosed when subtle symptoms are not recognized. The International Association for the Study of Pain supports the use of sympathetic blocks to reduce sympathetic nervous system over-activity and relieve complex regional pain symptoms. Educational reviews promote stellate ganglion blockade as beneficial. Three blocks were given at 8, 10 and 13 months after the initial injury under local anesthesia and sterile conditions. Physiotherapeutic input was delivered under block conditions to maximize joint and tissue mobility and facilitate restoration of function. The authors concluded that this case demonstrated the need for practitioners from all disciplines to be able to identify the clinical characteristics of complex regional pain syndrome to instigate immediate treatment and supports the notion that stellate ganglion blockade is preferable to upper limb intravenous regional anesthetic block for refractory index finger pain associated with complex regional pain syndrome.

      An UpToDate review on “Prevention and management of complex regional pain syndrome in adults” (Abdi, 2014) states that “Local sympathetic blocks (e.g., stellate ganglion block) with local anesthetic, while of unproven benefit in terms of the long-term outcome, nevertheless may provide a short-term decrease in pain that can be diagnostically useful and that can help with mobilization of the affected limb. The author has experience in using clonidine in combination with local anesthetics for stellate ganglion and lumbar sympathetic nerve blocks successfully, but its value needs to be systematically studied. Stellate ganglion blocks may be performed at one week intervals and may be repeated several times. This treatment is abandoned if an immediate response (e.g., improved temperature and decreased pain) does not occur following the first or second nerve block”.

      Connolly et al (2015) examined the available literature and synthesized published data concerning the treatment of CRPS with ketamine. The search was conducted utilizing the databases Medline, Embase and the Cochrane Central Registry of Controlled Trials. All relevant articles were systematically reviewed. The search yielded 262 articles, 45 of which met the inclusion/exclusion criteria. Of those included, 6 were reviews, 5 were randomized placebo-controlled trials, 13 were observational studies, and 21 were case reports. The authors concluded that there is no high quality evidence available evaluating the effectiveness of ketamine for CRPS and all manuscripts examined in this review were of moderate to low quality. They stated that there is currently only weak evidence supporting the effectiveness of ketamine for CRPS, yet there is clearly a rationale for definitive study.

      In a Cochrane review, Straube et al (2013) stated that the concept that many neuropathic pain syndromes (traditionally this definition would include CRPS) are "sympathetically maintained pains" has historically led to treatments that interrupt the sympathetic nervous system. Chemical sympathectomies use alcohol or phenol injections to destroy ganglia of the sympathetic chain, while surgical ablation is performed by open removal or electrocoagulation of the sympathetic chain or by minimally invasive procedures using thermal or laser interruption. These investigators reviewed the evidence from randomized, double blind, controlled trials on the safety and effectiveness of chemical and surgical sympathectomy for neuropathic pain, including CRPS. Sympathectomy may be compared with placebo (sham) or other active treatment, provided both participants and outcome assessors are blind to treatment group allocation. On July 2, 2013, these investigators searched CENTRAL, MEDLINE, EMBASE, and the Oxford Pain Relief Database. They reviewed the bibliographies of all randomized trials identified and of review articles and also searched 2 clinical trial databases, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, to identify additional published or unpublished data. They screened references in the retrieved articles and literature reviews and contacted experts in the field of neuropathic pain. Randomized, double-blind, placebo or active controlled studies assessing the effects of sympathectomy for neuropathic pain and CRPS were selected for analysis. Two review authors independently assessed trial quality and validity, and extracted data. No pooled analysis of data was possible. Only 1 study satisfied the inclusion criteria, comparing percutaneous radiofrequency thermal lumbar sympathectomy with lumbar sympathetic neurolysis using phenol in 20 participants with CRPS. There was no comparison of sympathectomy versus sham or placebo. No dichotomous pain outcomes were reported. Average baseline scores of 8 to 9/10 on several pain scales fell to about 4/10 initially (1 day) and remained at 3 to 5/10 over 4 months. There were no significant differences between groups, except for "unpleasant sensation", which was higher with radiofrequency ablation. One participant in the phenol group experienced post sympathectomy neuralgia, while 2 in the radiofrequency group and 1 in the phenol group complained of paraesthesia during needle positioning. All participants had soreness at the injection site. The authors concluded that the practice of surgical and chemical sympathectomy for neuropathic pain and CRPS was based on very little high quality evidence. Sympathectomy should be used cautiously in clinical practice, in carefully selected patients, and probably only after failure of other treatment options. In these circumstances, establishing a clinical register of sympathectomy may help to inform treatment options on an individual patient basis.

      In a review on “Complex regional pain syndrome”, Birklein et al (2015) states the following:

      • Magnetic resonance imaging (MRI) is helpful for eliminating differential diagnoses but not for diagnosing CRPS.
      • Quantitative sensory testing (QST) is not suitable for making a diagnosis.
      • Botulinum has very limited effects
      • Gabapentin might have a marginal but clinically unimportant effectiveness
      • The value of IV immunoglobulins needs to be confirmed

      Guidelines from the Royal College of Physicians on complex regional pain syndrome (Goebel et al, 2012) state that amputation should not be used to provide pain relief in CRPS. Amputation may worsen CRPS, with CRPS occuring in the stump.. Amputation may be considered in rare cases of intractable infection of the infected limb.

      Ketamine for the Treatment of Complex Regional Pain Syndrome

      Oaklander and Horowitz (2015) stated that CRPS is the current consensus-derived name for a syndrome usually triggered by limb trauma. Required elements include prolonged, disproportionate distal-limb pain and microvascular dysregulation (e.g., edema or color changes) or altered sweating. CRPS-II (formerly "causalgia") describes patients with identified nerve injuries. CRPS-I (formerly "reflex sympathetic dystrophy") describes most patients who lack evidence of specific nerve injuries. Diagnosis is clinical and the pathophysiology involves combinations of small-fiber axonopathy, microvasculopathy, inflammation, and brain plasticity/sensitization. Females have much higher risk and workplace accidents are a well-recognized cause. Inflammation and dysimmunity, perhaps facilitated by injury to the blood-nerve barrier, may contribute. Most patients, particularly the young, recover gradually, but treatment can speed healing. Evidence of effectiveness is strongest for rehabilitation therapies (e.g., graded-motor imagery), neuropathic pain medications, and electric stimulation of the spinal cord, injured nerve, or motor cortex. Investigational treatments include ketamine, botulinum toxin, immunoglobulins, and transcranial neuromodulation. Non-recovering patients should be re-evaluated for neuro-surgically treatable causal lesions (nerve entrapment, impingement, infections, or tumors) and treatable potentiating medical conditions, including polyneuropathy and circulatory insufficiency.

      Xu and colleagues (2016) noted that CRPS remains a challenging clinical pain condition. Multi-disciplinary approaches have been advocated for managing CRPS. Compared with spinal cord stimulation and intrathecal targeted therapy, IV treatments are less invasive and less costly. These investigators reviewed the literature on IV therapies and determine the level of evidence to guide the management of CRPS. They searched PubMed, Embase, Scopus, and the Cochrane databases for articles published on IV therapies of CRPS up through February 2015. The search yielded 299 articles, of which 101 were deemed relevant by reading the titles and 63 by reading abstracts. All these 63 articles were retrieved for analysis and discussion. These researchers evaluated the relevant studies and provided recommendations according to the level of evidence. The authors concluded that there is evidence to support the use of IV bisphosphonates, immunoglobulin, ketamine, or lidocaine as valuable interventions in selected patients with CRPS. However, they stated that high-quality studies are needed to further evaluate the safety, effectiveness, and cost-effectiveness of IV therapies for CRPS.

      Kim et al (2016) examined the effects of long-term frequent ketamine treatment on cognitive function in [AQ-A] CRPS patients. A total of 30 CRPS patients were divided into 2 groups based on both the duration and frequency of ketamine treatment the long-term frequent ketamine treatment (LF) group (n = 14) and the non-LF group (n = 16). Participants were asked to complete a questionnaire packet including demographic and clinical characteristics and potential variables affecting cognitive function. Then, they performed the neuropsychological test. Results indicated that the LF group performed significantly poorer than the non-LF group on the digit span, digit symbol, Controlled Oral Word Association Test, and Trail Making Test, but not the Stroop task. The authors concluded that patients with CRPS receiving long-term frequent ketamine treatment showed impairment in cognitive function (specifically executive function) compared with those who do not. These findings may have implications for clinical assessment and rehabilitation of cognitive function in CRPS patients.

      Goldberg et al (2005) reported on the effectiveness of low-dose outpatient ketamine infusion for the treatment of CRPS diagnosed by International Association for the Study of Pain criteria in patients who have failed conservative treatment. Patients diagnosed with CRPS by a single neurologist were assigned to receive a 10-day outpatient infusion of ketamine supervised by an anesthesiologist/pain management specialist. The infusion was administered in a short procedure unit after each patient had been instructed on how to complete a pain questionnaire. Monitoring consisted of continuous ECG, pulse oximetry, and non-invasive blood pressure every 15 mins. Patients made journal entries each day prior to the infusion of 40 to 80 mg of ketamine. Subjects were also asked to rate their pain intensity using a verbal analog scale of 0 to 10 and the affective component using a verbal scale of 0 to 4. There was a significant reduction in pain intensity from initiation of infusion (day 1) to the 10th day, with a significant reduction in the percentage of patients experiencing pain by day 10 as well as a reduction in the level of their "worst" pain. The nadirs of pain were lower by day 10 with a significant reduction in the incidence of "punishing pain". Moreover, there was a significant improvement in the ability to initiate movement by the 10th day. The authors concluded that a 4-hr ketamine infusion escalated from 40 to 80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation. They also stated that although pain data showed some variability, the results are encouraging and point to the need for additional studies.

      Sigtermans et al (2009) evaluated if ketamine improves pain in CRPS-1 patients. A total of 60 patients (48 females) with severe pain participated in a double-blind randomized placebo-controlled parallel-group trial. Patients were given a 4.2-day intravenous infusion of low-dose ketamine (n = 30) or placebo (n = 30) using an individualized step-wise tailoring of dosage based on effect (pain relief) and side effects (nausea/vomiting/psychomimetic effects). The primary outcome of the study was the pain score (numerical rating score: 0 to 10) during the 12-week study period. The median (range) disease duration of the patients was 7.4 (0.1 to 31.9) years. At the end of infusion, the ketamine dose was 22.2 +/- 2.0 mg/hr/70 kg body weight. Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo (p < 0.001). The lowest pain score was at the end of week 1: ketamine 2.68 +/- 0.51, placebo 5.45 +/- 0.48. In week 12, significance in pain relief between groups was lost (p = 0.07). Treatment did not cause functional improvement. Patients receiving ketamine more often experienced mild-to-moderate psychomimetic side effects during drug infusion (76 % versus 18 %, p < 0.001). The authors concluded that in a population of mostly chronic CRPS-1 patients with severe pain at baseline, a multiple day ketamine infusion resulted in significant pain relief without functional improvement. However, it is important to note that the significance in pain relief between groups was lost in week 12.

      1. its small size (n = 26)
      2. non-stratification of patients either by length of time with the illness or by the temperature of the affected area and
      3. lack of a cross-over arm.

      In a preliminary report, Puchalski and Zyluk (2016) noted that chronic, refractory CRPS remains very difficult to treat. A sub-anesthetic low-dose ketamine has shown promise in advanced CRPS. These investigators examined the efficacy of ketamine in anesthetic dosage in chronic, refractory CRPS patients that had failed available standard therapies. A total of 5 women, mean age of 34 years with long-standing, a mean of 8 years', CRPS received ketamine in anesthetic dosage over 10 days. The patients received 1 to 5 ketamine courses. The effect of gradual pain reduction was observed beginning on the 4(th)-5(th) day of treatment, associated with a decrease in the intensity of the allodynia (pain at light touch). No improvement in function (finger range of motion, grip strength) of the affected hands was noted in any patient. This beneficial analgesic effect was confined to 1.5 to 2.5 months after treatment and then pain relapsed to the baseline level. The authors concluded that the results of this study showed a short-term analgesic effect for this therapy, with no effect on movement and function of the affected limbs. Nevertheless, this method brings hope to the most severely ill patients who cannot be offered any other reasonable therapeutic option.

      In a systematic review on “Intravenous therapies for complex regional pain syndrome”, Xu et al (2016) concluded that “high-quality studies are needed to further evaluate the safety, efficacy, and cost-effectiveness of IV therapies (e.g., bisphosphonates, immunoglobulin, ketamine, or lidocaine) for CRPS.

      In a meta-analysis, Zhao and colleagues (2018) examined the efficacy of ketamine in the treatment of CRPS. A search of Embase, PubMed, Web of Knowledge, Cochrane, Clinical Trial.gov , and FDA.gov between January 1, 1950 and August 1, 2017 was conducted to evaluate ketamine infusion therapy in the treatment of CRPS. These researchers selected RCTs or cohort studies for meta-analyses. I2 index estimates were calculated to test for variability and heterogeneity across the included studies. The primary outcome is pain relief. The effect of ketamine treatment for CRPS was assessed by 0 to 10 scale numerical rating pain score. The secondary outcome is the pain relief event rate, which is defined as the percentage of participants who achieved 30 % or higher pain relief in each of the qualified studies. The meta-analysis results showed that the ketamine treatment led to a decreased mean of pain score in comparison to the self-controlled baseline (p < 0.000001). However, there was a statistical significance of between-study heterogeneity. The immediate pain relief event rate was 69 % (95 % CI: 53 % to 84 %). The pain relief event rate at the 1 to 3 months follow-ups was 58 % (95 % CI: 41 % to 75 %). The current available studies regarding ketamine infusion for CRPS were reviewed, and meta-analyses were conducted to evaluate the efficacy of ketamine infusion in the treatment of CRPS. The authors concluded these findings suggested that ketamine infusion can provide clinically effective pain relief in short-term for less than 3 months. However, because of the high heterogeneity of the included studies and publication bias, additional RCTs and standardized multi-center studies are needed to confirm this conclusion. Furthermore, studies are needed to prove long-term efficacy of ketamine infusion in the treatment of CRPS.

      Furthermore, an UpToDate review on “Complex regional pain syndrome in adults: Prevention and management” (Abdi, 2018) stated that “Other pharmacologic treatments for CRPS with limited evidence include alpha adrenergic drugs, ketamine, and intravenous immune globulin”.

      Ketamine for the Treatment of Depression

      Abdallah et al (2015) stated that ketamine is the prototype for a new generation of glutamate-based antidepressants that rapidly alleviate depression within hours of treatment. Over the past decade, there has been replicated evidence demonstrating the rapid and potent anti-depressant effects of ketamine in treatment-resistant depression. Moreover, pre-clinical and biomarker studies have begun to elucidate the mechanism underlying the rapid antidepressant effects of ketamine, offering a new window into the biology of depression and identifying a plethora of potential treatment targets. These investigators discussed the efficacy, safety, and tolerability of ketamine, summarized the neurobiology of depression, reviewed the mechanisms underlying the rapid antidepressant effects of ketamine, and discussed the prospects for next-generation rapid-acting anti-depressants. The authors concluded that although a single infusion of ketamine appears to be safe, the long-term safety of repeated ketamine dosing is not fully known. They stated that as a prototype for rapid-acting anti-depressants, ketamine has provided an exciting new direction that may offer hope of rapid therapeutics for patients who are suffering from depression.

      Sanacora and Schatzberg (2015) noted that large “real world” studies demonstrating the limited effectiveness and slow onset of clinical response associated with the existing anti-depressant medications has high-lighted the need for the development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing anti-depressant treatments with fundamentally novel mechanisms of action over the past 6 decades, leaving the field wary and skeptical about any new developments. However, a series of relatively small proof-of-concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, anti-depressant effects can be achieved with a single administration of ketamine. These researchers stated that “We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the anti-depressant action”. These investigators shared their opinions on these issues and discussed paths to move the field forward. The authors concluded that “we remain in disagreement over what we have learned from our experience with ketamine and another NMDAR drugs to date for the treatment of mood disorders. We agree that there is clear evidence that ketamine can produce rapid transient antidepressant-like effects, but remain divergent in our opinions on the mechanisms mediating these effects and the potential to act on what we know to initiate novel treatment approaches or suggest novel pathways for drug development. We agree that it is premature to conclude that any single mechanism is solely responsible for the antidepressant response, and that the response is potentially mediated through complex pathways downstream from ketamine’s direct actions at any receptor. We strongly agree that pre-clinical studies should explore potential alternative MoAs [mechanism of actions] and that more clinical studies are needed to clearly establish the true clinical effectiveness and safety of the treatment before it is made widely available in the clinical setting”.

      In a “Letter to the Editor”, da Frota Ribeiro et al (2016) stated that “Mounting evidence from a series of small clinical trials and case series suggests ketamine can have rapid and robust antidepressant and possibly anti-suicidal effects in patients who did not respond to standard treatment options. However, because of the variable psychotomimetic effects of ketamine in healthy volunteers and exacerbation of previously experienced positive symptoms in schizophrenic volunteers, patients previously experiencing psychotic features have been excluded from the reported studies and trials. We have used ketamine as an anti-depressant on several occasions in patients with severe treatment-resistant major depressive episodes with good results. Recently, after seriously considering the risks and benefits of providing off-label ketamine treatment (0.5 mg/kg continuous intravenous infusion over 40 min) based on this knowledge, we treated two patients with psychotic features complicating severe depressive episodes. To our knowledge, this is the first report describing the use of ketamine as treatment in patients with a history of psychosis …. Further evidence is needed to establish the efficacy of ketamine in the treatment of mood disorders and the safety of providing the treatment to patients with psychotic features before broadening its use in clinical settings, especially when considering repeated administrations. However, this very small case series suggests that it may be possible to study patients with the diagnosis of major depression with psychotic features in future clinical trials this is especially important because these patients are often among the most severely depressed and treatment resistant patients seen in the clinical setting”.

      Compression Sleeve for the Treatment of Complex Regional Pain Syndrome

      An UpToDate review on “Prevention and management of complex regional pain syndrome in adults” (Abdi, 2016) does not mention the use of compression sleeve as a management tool.

      Intrathecal Adenosine and Clonidine for the Treatment of Complex Regional Pain Syndrome

      Rauck et al (2015) stated that pre-clinical data suggested that intrathecal adenosine and clonidine reduced hypersensitivity, but only clonidine reduced pain. These researchers tested the effects of these interventions in patients with chronic pain. A total of 22 subjects with pain and hyperalgesia in a lower extremity from CRPS were recruited in a double-blind cross-over study to receive intrathecal adenosine, 2 mg, or clonidine, 100 μg. Primary outcome measure was proportion with greater than or equal to 30 % reduction in pain 2 hours after injection, and secondary measures were pain report, areas of hypersensitivity, and temporal summation to heat stimuli. Treatments did not differ in the primary outcome measure (10 met success criterion after clonidine administration and 5 after adenosine administration), although they did differ in pain scores over time, with clonidine having a 3-fold greater effect (p = 0.014). Both drugs similarly reduced areas of hyperalgesia and allodynia by approximately 30 % and also inhibited temporal summation. The percentage change in pain report did not correlate with the percentage change in areas of hyperalgesia (p = 0.09, r = 0.08) or allodynia (p = 0.24, r = 0.24) after drug treatment. Both intrathecal adenosine and clonidine acutely inhibited experimentally-induced and clinical hypersensitivity in patients with CRPS. The authors concluded that although these drugs did not differ in analgesia by the primary outcome measure, their difference in effect on pain scores over time and lack of correlation between effect on pain and hypersensitivity suggested that analgesia does not parallel anti-hyperalgesia with these treatments.

      Furthermore, an UpToDate review on “Prevention and management of complex regional pain syndrome in adults” (Abdi, 2016) does not mention the use of intrathecal adenosine and clonidine as a therapeutic option.

      Movement Representation Techniques for the Treatment of Complex Regional Pain Syndrome

      Thieme et al (2016) noted that relatively new evidence suggested that movement representation techniques (i.e., therapies that use the observation and/or imagination of normal pain-free movements, such as mirror therapy, motor imagery, or movement and/or action observation) might be effective in reduction of some types of limb pain. These researchers summarized the evidence regarding the effectiveness of those techniques by performing a systematic review with meta-analysis. They searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, AMED, PsychINFO, Physiotherapy Evidence Database, and OT-seeker up to August 2014 and hand-searched further relevant resources for RCTs that studied the effectiveness of movement representation techniques in reduction of limb pain. The outcomes of interest were pain, disability, and quality of life. Study selection and data extraction were performed by 2 reviewers independently. They included 15 trials on the effects of mirror therapy, (graded) motor imagery, and action observation in patients with CRPS, phantom limb pain, post-stroke pain, and non-pathological (acute) pain. Overall, movement representation techniques were found to be effective in reduction of pain (standardized mean difference [SMD] = -0.82, 95 % CI: -1.32 to -0.31, p = 0.001) and disability (SMD = 0.72, 95 % CI: 0.22 to 1.22, p = 0.004) and showed a positive but non-significant effect on quality of life (SMD = 2.61, 95 % CI: -3.32 to 8.54, p = 0.39). Especially mirror therapy and graded motor imagery should be considered for the treatment of patients with CRPS. Furthermore, the results indicated that motor imagery could be considered as a potential effective treatment in patients with acute pain after trauma and surgery. To-date, there is no evidence for a pain-reducing effect of movement representation techniques in patients with phantom limb pain and post-stroke pain other than CRPS. The authors concluded that they synthesized the evidence for the effectiveness of movement representation techniques (i.e., motor imagery, mirror therapy, or action observation) for treatment of limb pain. They stated that these findings suggested effective pain reduction in some types of limb pain further research should address specific questions on the optimal type and dose of therapy.

      Graded Motor Imagery and Mirror Therapy

      Mendez-Rebolledo et al (2017) stated that graded motor imagery (GMI) and mirror therapy (MT) is thought to improve pain in patients with CRPS types 1 and 2. However, the evidence is limited and analysis are not independent between types of CRPS. These investigators analyzed the effects of GMI and MT on pain in independent groups of patients with CRPS types 1 and 2. Searches for literature published between 1990 and 2016 were conducted in databases RCTs that compared GMI or MT with other treatments for CRPS types 1 and 2 were included. A total of 6 articles met the inclusion criteria and were classified from moderate to high quality. The total sample was composed of 171 participants with CRPS type 1 3 studies presented GMI with 3 components and 3 studies only used the MT. The studies were heterogeneous in terms of sample size and the disorders that triggered CRPS type 1. There were no trials that included participants with CRPS type 2. The authors concluded that GMI and MT can improve pain in patients with CRPS type 1 however, there is insufficient evidence to recommend these therapies over other treatments given the small size and heterogeneity of the studied population.

      Furthermore, a Cochrane review on "Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II" (Smart et al, 2016) stated that there is very low quality evidence that graded motor imagery (GMI 2 trials, 49 subjects) may be useful for improving pain and functional disability at long-term (6 months) follow-up in people with CRPS I compared to usual care plus physiotherapy. In a Cochrane review, Smart and colleagues (2016) examined the effectiveness of physiotherapy interventions for treating the pain and disability associated with CRPS types I and II. These investigators searched the following databases from inception up to February 12, 2015: CENTRAL (the Cochrane Library), Medline, Embase, CINAHL, PsycINFO, LILACS, PEDro, Web of Science, DARE and Health Technology Assessments, without language restrictions, for RCTs of physiotherapy interventions for treating pain and disability in people CRPS. They also searched additional online sources for unpublished trials and trials in progress. These researchers included RCTs of physiotherapy interventions (including manual therapy, therapeutic exercise, electrotherapy, physiotherapist-administered education and cortically directed sensory-motor rehabilitation strategies) employed in either a stand-alone fashion or in combination, compared with placebo, no treatment, another intervention or usual care, or of varying physiotherapy interventions compared with each other in adults with CRPS I and II. The primary outcomes of interest were patient-centered outcomes of pain intensity and functional disability. Two review authors independently evaluated those studies identified through the electronic searches for eligibility and subsequently extracted all relevant data from the included RCTs. Two review authors independently performed “risk of bias” assessments and rated the quality of the body of evidence for the main outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The authors included 18 RCTs (739 participants) that tested the effectiveness of a broad range of physiotherapy-based interventions. Overall, there was a paucity of high quality evidence concerning physiotherapy treatment for pain and disability in people with CRPS I. Most included trials were at “high” risk of bias (15 trials) and the remainder were at “unclear” risk of bias (3 trials). The quality of the evidence was very low or low for all comparisons, according to the GRADE approach. These researchers found very low quality evidence that GMI (2 trials, 49 participants) may be useful for improving pain (0 to 100 VAS) (MD -21.00, 95 % CI: -31.17 to -10.83) and functional disability (11-point numerical rating scale) (MD 2.30, 95 % CI: 1.12 to 3.48), at long-term (6 months) follow-up, in people with CRPS I compared to usual care plus physiotherapy very low quality evidence that multi-modal physiotherapy (1 trial, 135 participants) may be useful for improving “impairment” at long-term (12 month) follow-up compared to a minimal “social work” intervention and very low quality evidence that MT (20 trials, 72 participants) provided clinically meaningful improvements in pain (0 to 10 VAS) (MD 3.4, 95 % CI: -4.71 to -2.09) and function (0 to 5 functional ability subscale of the Wolf Motor Function Test) (MD -2.3, 95 % CI: -2.88 to -1.72) at long-term (6 month) follow-up in people with CRPS I post stroke compared to placebo (covered mirror). There was low to very low quality evidence that tactile discrimination training, stellate ganglion block via ultrasound and pulsed electromagnetic field therapy compared to placebo, and manual lymphatic drainage combined with and compared to either anti-inflammatories and physical therapy or exercise are not effective for treating pain in the short-term in people with CRPS I. Laser therapy may provide small clinically insignificant, short-term, improvements in pain compared to interferential current therapy in people with CRPS I adverse events (AEs) were only rarely reported in the included trials. No trials including participants with CRPS II met the inclusion criteria of this review. The authors concluded that the best available data showed that GMI and MT may provide clinically meaningful improvements in pain and function in people with CRPS I although the quality of the supporting evidence is very low. Evidence of the effectiveness of multi-modal physiotherapy, electrotherapy and manual lymphatic drainage for treating people with CRPS types I and II is generally absent or unclear. They stated that large scale, high quality RCTs are needed to test the effectiveness of physiotherapy-based interventions for treating pain and disability of people with CRPS I and II.

      Dorsal Root Ganglion Stimulation

      Song and colleagues (20114) reviewed the evidence supporting the use of spinal cord stimulation (SCS) for the approved indications and discussed some emerging neuromodulation technologies that may potentially address pain conditions that traditional SCS has difficulty addressing. These researchers noted that SCS has been reported to be superior to conservative medical management and re-operation when dealing with pain from failed back surgery syndrome. It has also demonstrated clinical benefit in CRPS, critical limb ischemia, and refractory angina pectoris. Furthermore, several cost analysis studies have demonstrated that SCS is cost-effective for these approved conditions. Despite the lack of a comprehensive mechanism, the technology and the complexity in which SCS is being utilized is growing. Newer devices are targeting axial low back pain and foot pain, areas that have been reported to be more difficult to treat with traditional SCS. Percutaneous hybrid paddle leads, peripheral nerve field stimulation, nerve root stimulation, dorsal root ganglion stimulation (DRGS), and high frequency stimulation are actively being refined to address axial low back pain and foot pain. High frequency stimulation is unique in that it provides paresthesia free analgesia by stimulating beyond the physiologic frequency range. The preliminary results have been mixed and a large RCT is underway to evaluate the future of this technology. Other emerging technologies, including DRGS and hybrid leads, also showed some promising preliminary results in non-randomized observational trials. The authors concluded that SCS has demonstrated clinical efficacy in RCTs for the approved indications. In addition, several open-label observational studies on peripheral nerve field stimulation, hybrid leads, DRGS, and high frequency stimulation showed some promising results. However, large RCTs demonstrating clear clinical benefit are needed to gain evidence based support for their use.

      Liem and associates (2015) stated that DRGS is a new therapy for treating chronic neuropathic pain. Previous work has demonstrated the effectiveness of DRGS for pain associated with failed back surgery syndrome, CRPS, chronic post-surgical pain, and other etiologies through 6 months of treatment this report described the maintenance of pain relief, improvement in mood, and quality of life through 12 months. Subjects with intractable pain in the back and/or lower limbs were implanted with an active neurostimulator device. Up to 4 percutaneous leads were placed epidurally near DRGs. Subjects were tracked prospectively for 12 months. Overall, pain was reduced by 56 % at 12 months post-implantation, and 60 % of subjects reported greater than 50 % improvement in their pain. Pain localized to the back, legs, and feet was reduced by 42 %, 62 %, and 80 %, respectively. Measures of quality of life (QOL) and mood were also improved over the course of the study, and subjects reported high levels of satisfaction. More importantly, excellent pain-paresthesia overlap was reported, remaining stable through 12 months. The authors concluded that despite methodological differences in the literature, DRGS appeared to be comparable to traditional SCS in terms of pain relief and associated benefits in mood and QOL. Its benefits may include the ability to achieve precise pain-paresthesia concordance, including in regions that are typically difficult to target with SCS, and to consistently maintain that coverage over time. This was an industry-sponsored study additional independent data from well-designed studies are needed to ascertain the effectiveness of DRGS.

      In a prospective case series, Van Buyten and co-workers (2015) examined the effects of DRGS for the management of CRPS. A total of 11 subjects diagnosed with uni- or bi-lateral lower-extremity CRPS were recruited as part of a larger study involving chronic pain of heterogeneous etiologies. Quadripolar epidural leads of a newly developed neurostimulation system were placed near lumbar DRGs using conventional percutaneous techniques. The neurostimulators were trialed 8 were successful and permanently implanted and programed to achieve optimal pain-paresthesia overlap. All 8 subjects experienced some degree of pain relief and subjective improvement in function, as measured by multiple metrics. One month after implantation of the neurostimulator, there was significant reduction in average self-reported pain to 62 % relative to baseline values. Pain relief persisted through 12 months in most subjects. In some subjects, edema and trophic skin changes associated with CRPS were also mitigated and function improved DRGS was able to provide excellent pain-paresthesia concordance in locations that are typically hard to target with traditional SCS, and the stimulation reduced the area of pain distributions. The authors concluded that DRGS appeared to be a promising option for relieving chronic pain and other symptoms associated with CRPS.

      In a single-case study, van Bussel and associates (2015) reported on the effectiveness of DRG stimulation in a patient with CRPS type I of the knee. The subject was a 48-year old woman with CRPS type I of the right knee, diagnosed according to the Budapest criteria set, received DRG stimulation for intractable CRPS type I of the knee. After a successful trial period with 3 DRG stimulation leads on spinal levels L2, L3, and L4 (covering 90 % of the painful area of her knee), a definitive pulse generator was implanted. Three months after implantation, the entire painful area was covered, and the patient reported a numeric rating scale score of 1 to 2. The authors concluded that placement of 3 DRG stimulation leads at levels L2, L3, and L4 in a patient with intractable CRPS type I of the knee resulted in major pain relief. Moreover, they recommended further investigation of the effect of DRG stimulation on pain due to CRPS of the knee.

      Garg and Danesh (2015) presented a case where DRGS was performed to treat CRPS in the distal upper extremity. A 43-year old female underwent a right elbow arthroscopy with open reduction and internal fixation after sustaining a radial head fracture. Several months after her surgery, she experienced hyperesthesia, skin color changes, decreased range of motion (ROM), weakness distal to the right olecranon, and was diagnosed with CRPS. Aggressive physical therapy, non-steroidal anti-inflammatory drugs (NSAIDs), and neuropathic agents provided mild relief. Open capsular release, hardware removal, and chondral debridement of the elbow did not provide alleviation. A diagnostic stellate ganglion block provided complete relief for 2 weeks. A therapeutic block allowed 1 day of relief, followed by recurrence of her symptoms. She underwent an SCS trial for treatment. Scar tissue in the posterior epidural space prevented catheter advancement, causing it to exit the C6 foramen. Incidental stimulation of the DRG occurred. On follow-up, patient reported greater than 70 % relief of her pain. On the VAS, her maximal pain decreased from 8/10 to 4/10, with resolution of her initial symptoms and ability to perform all of her activities of daily living (ADL). The authors concluded that this was the only reported case of utilizing DRGS for CRPS of the distal upper extremity DRGs appeared to be an effective option for targeting painful areas in CRPS. These preliminary findings need to be validated by well-designed studies.

      Deer and colleagues (2017) noted that animal and human studies showed that electrostimulation of DRG neurons may modulate neuropathic pain signals. ACCURATE, a pivotal, prospective, multi-center, randomized-comparative effectiveness trial, was conducted in 152 subjects diagnosed with CRPS or causalgia in the lower extremities. Subjects received DRGS or DCS. The primary end-point was a composite of safety and effectiveness at 3 months and subjects were assessed through 12 months for long-term outcomes and adverse events (AEs). The pre-defined primary composite end-point of treatment success was met for subjects with a permanent implant who reported 50 % or greater decrease in VAS from pre-implant baseline and who did not report any stimulation-related neurological deficits. No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving greater than or equal to 50 % pain relief and treatment success was greater in the DRG arm (81.2 %) versus the DCS arm (55.7 %, p < 0.001) at 3 months. Device-related and serious AEs were not different between the 2 groups DRGS also demonstrated greater improvements in QOL and psychological disposition. Finally, subjects using DRGS reported less postural variation in paresthesia (p < 0.001) and reduced extraneous stimulation in non-painful areas (p = 0.014), indicating DRGS provided more targeted therapy to painful parts of the lower extremities. The authors concluded that as the largest prospective, randomized comparative effectiveness trial to-date, the results showed DRGS provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS. These encouraging findings need to be validated by well-designed RCTs.

      Furthermore, an UpToDate review on “Complex regional pain syndrome in adults: Prevention and management” (Abdi, 2017) does not mention DRG stimulation as a management tool.

      Pulsed Radiofrequency

      In a case-series study, Albayrak and colleagues (2016) examined the effects of pulsed radiofrequency (PRF) applied to the DRG for treatment of post-stroke CRPS. Subjects were a 69-year old woman and a 48-year-old women who suffered post-stroke CRPS type 1. The patients had complete resolution of their symptoms, which was maintained at 10 and 5 months of follow-up. The authors concluded that the findings of these cases illustrated that PRF applied to cervical DRG might play a significant role in multi-modal approach of CRPS type 1 management after stroke. Moreover, they stated that further RCTs are needed to support this argument.

      Intravenous Immunoglobulin

      In a randomized, multi-center, double-blinded, placebo-controlled trial in 7 UK pain management centers, Goebel and colleagues (2017) examined if low-dose IVIG is effective for reducing pain in long-standing CRPS. Patients were eligible if they had moderate or severe long-standing CRPS that they had experienced for up to 5 years. Participants were randomly allocated to receive 0.5 g/kg IVIG, the active intervention, or visually indistinguishable 0.1 % albumin in saline placebo. Randomization was initiated by study sites via an independent online randomization system and was 1 : 1 with varying block sizes, stratified by study center. Subjects, investigators and assessors were blinded to group assignment. The study drug/placebo was infused intravenously at the study centers on day 1 and day 23 after randomization. The primary outcome was the 24-hour average pain intensity between day 6 and day 42, on an 11-point (0 to 10) numeric rating scale (NRS), compared between the groups. Outcomes were analyzed using a mixed-effects regression model that used 37 measurements of pain intensity (the primary outcome) per participant. All patients who received an infusion and provided any outcome were included in the intention-to-treat analysis. A total of 111 patients were recruited and assigned between August 27, 2013 and October 28, 2015 3 patients were excluded because they had been inappropriately randomized, 5 patients were withdrawn from the primary analysis because they provided no outcomes and 103 patients were analyzed for the primary outcome. The average pain score in the IVIG group was 0.27 units (95 % CI: 0.24 to 0.80 units) higher than in the placebo group. Therefore, there was no significant evidence of a treatment effect at the 5 % level and there was no significant difference between groups 6 serious AEs but no suspected unexpected serious adverse reactions were reported during the blinded and open-label phase. The authors concluded that low-dose IVIG was not effective in relieving pain in patients with moderate-to-severe CRPS of 1 to 5 years’ duration.

      Free-Flap Surgery and Vein Wrapping

      In a single-case study, Seo and colleagues (2017) reported the results of free-flap surgery and vein wrapping of the superficial peroneal nerve surgery for the treatment of CRPS. A 39-year old man underwent an arthroscopic synovectomy and open repair of the anterior talofibular ligament at the ankle, and pain developed after surgery. The patient did not show improvement following conservative treatment. A pain clinician inserted a spinal cord stimulator. Even though his symptoms improved by 50 %, the focal symptoms around the left ankle remained. After undergoing adhesiolysis operation, the patient’s symptoms did not improve, and they worsened further under conservative management for an additional 10 months. These investigators excised the hypersensitive skin and cover the defect with distant healthy tissue to relieve the patient’s symptoms. At the 3 years follow-up after flap surgery, intractable allodynia at the flap site disappeared. Severe symptoms developed around the surgical scar the pain was not diffuse. The patient was diagnosed with CRPS type II based on these clinical findings. The authors noted that vein wrapping of the peripheral nerves was first described by Masear et al. It can protect nerves by inhibiting tissue adhesion, improving the gliding of the nerve, and decreasing scarring within the nerve trunk. However, hypersensitivity did not disappear on the distant area of the flap site in this case. Thus, the effect of vein wrapping of the nerve was doubtful in this case. The authors concluded that careful consideration in replacing the hypersensitive skin with healthy tissue by the free-flap surgery is recommended. They stated that this can be one of the treatment methods for the CRPS type II. These preliminary findings need to be validated by well-designed studies.

      Transcranial Direct Current Stimulation / Transcranial Magnetic Stimulation

      In a randomized, proof of concept study, Lagueux and colleagues (2018) examined the effectiveness of graded motor imagery (GMI) plus active transcranial direct current stimulation (tDCS) compared with the GMI plus sham tDCS in the treatment of CRPS type I. A total of 22 patients (n = 11 per group) were randomly assigned to the experimental (GMI + tDCS) or placebo (GMI + sham tDCS) group. GMI treatments lasted 6 weeks anodal tDCS was applied over the motor cortex for 5 consecutive days during the first 2 weeks and once-weekly thereafter. Changes in pain perception, QOL, kinesiophobia, pain catastrophizing, anxiety and mood were monitored after 6 weeks of treatment (T1) and 1-month post-treatment (T2). GMI + tDCS induced no statistically significant reduction in pain compared with GMI + sham tDCS. Although these researchers observed significant group differences in kinesiophobia (p = 0.012), pain catastrophizing (p = 0.049), and anxiety (p = 0.046) at T1, these improvements were not maintained at T2 and did not reached a clinically significant difference. The authors found no added value of tDCS combined with GMI treatments for reducing pain in patients with chronic CRPS. However, given that GMI + sham tDCS induced no significant change, further studies comparing GMI + tDCS and tDCS alone are needed to further document tDCS's effect in CRPS.

      Nardone and associates (2018) noted that the sensory and motor cortical representation corresponding to the affected limb is altered in patients with CRPS. Transcranial magnetic stimulation (TMS) represents a useful non-invasive approach for studying cortical physiology. If delivered repetitively, TMS can also modulate cortical excitability and induce long-lasting neuroplastic changes. In this review, these investigators performed a systematic search of all studies using TMS to explore cortical excitability/plasticity and repetitive TMS (rTMS) for the treatment of CRPS. Literature searches were conducted using PubMed and Embase. A total of 8 articles matching the inclusion criteria were identified 114 patients (76 females and 38 males) were included in these studies. Most of them have applied TMS in order to physiologically characterize CRPS type I. Changes in motor cortex excitability and brain mapping have been reported in CRPS-I patients. Sensory and motor hyper-excitability were in the most studies bilateral and likely involve corresponding regions within the central nervous system rather than the entire hemisphere. Conversely, sensorimotor integration and plasticity were found to be normal in CRPS-I. TMS examinations also revealed that the nature of motor dysfunction in CRPS-I patients differed from that observed in patients with functional movement disorders, limb immobilization, or idiopathic dystonia. The authors concluded that TMS studies may thus lead to the implementation of correct rehabilitation strategies in CRPS-I patients. They stated that 2 studies have begun to therapeutically use rTMS this non-invasive brain stimulation technique could have therapeutic utility in CRPS.. Moreover, these researchers stated that further well-designed studies are needed to corroborate initial findings.

      In a non-randomized, open-label, pilot trial, Gaertner and co-workers (2018) employed a TMS protocol that may lead to significant pain relief for upper and lower extremity CRPS. This study entailed 21 participants. These investigators individualized TMS coil positioning over motor cortex of somatic pain location, and administered intermittent theta-burst stimulation followed by 10-Hz high-frequency stimulation using a deeper targeting coil. They assessed response (greater than or equal to 30 % pain reduction) from a single session (n = 5) and 5 consecutive daily sessions (n = 12) and compared change in pain from baseline, after 1 treatment and 1-week post-treatment between groups using a mixed ANVOA. Both groups demonstrated significant pain reduction after 1 session and 1-week post-treatment however, no group differences were present. From a single session, 60 % of participants responded at Week 1. From 5 sessions, 58 % and 50 % of participants responded at Weeks 1 and 2, respectively 2 from each group achieved greater than 50 % pain reduction beyond 6 to 8 weeks. No serious AEs occurred. Although headache and nausea were the most common side-effects, these researchers urged careful monitoring to prevent seizures with this protocol. The authors concluded that they used a TMS protocol that, for the first time, led to significant pain relief in upper and lower extremity CRPS, and will soon examine this protocol in a larger, controlled trial.

      Miscellaneous Investigational Interventions

      Pickering and Morel (2018) noted that neuropathic pain is difficult to treat and is associated with a decline in QOL. Etiologies of neuropathic pain are numerous and a number of pathologies display neuropathic characteristics. Of the various N-methyl-d-aspartate antagonists that are alternatives to be recommended in 1st-line treatment of neuropathic pain, memantine has the safest side-effect profile and has long been approved in Alzheimer's disease. The review covered memantine studies in post-herpetic neuralgia, diabetic pain, post-operative pain, CRPS, chronic phantom limb pain, opioid-refractory pain and fibromyalgia. Results were inconclusive because of studies with poor levels of evidence, paucity of trials and small samples. Two recent randomized trials, however, showed significant efficacy of memantine: one demonstrated prophylactic effects against post-operative neuralgia and pain-associated psychological impairment in the other, memantine improved pain and cognition in fibromyalgia. Both studies found no side effects or AEs. The authors concluded that given the high rate of therapeutic failure in chronic states, often because of AEs, the excellent benefit/risk ratio of memantine in these pilot studies encouraged further exploration of this drug in neuropathic pain prevention and in fibromyalgia in larger-scale studies.

      Duong and colleagues (2018) stated that although multiple treatments have been advocated for CRPS, the levels of supportive evidence are variable and sometimes limited. These investigators provided a critical analysis of the evidence pertaining to the treatment of CRPS derived from recent RCTs. The Medline, Embase, Psychinfo, and CINAHL databases were searched to identify relevant RCTs conducted on human subjects and published in English between May 1, 2009 and August 24, 2017. The search yielded 35 RCTs of variable quality pertaining to the treatment of CRPS. Published trials continue to support the use of bisphosphonates and short courses of oral steroids in the setting of CRPS. Although emerging evidence suggested a therapeutic role for ketamine, memantine, intravenous immunoglobulin, epidural clonidine, intrathecal clonidine/baclofen/adenosine, aerobic exercise, mirror therapy, virtual body swapping, and dorsal root ganglion stimulation, further confirmatory RCTs are needed. Similarly, trials also suggested an expanding role for peripheral sympathetic blockade (i.e., lumbar/thoracic sympathetic, stellate ganglion, and brachial plexus blocks). The authors concluded that since their prior systematic review article (published in 2010), 35 RCTs related to CRPS have been reported. Nevertheless, the quality of trials remains variable thus, further research is needed to continue investigating possible treatments for CRPS.

      Bio-Electro-Magnetic-Energy-Regulation (BEMER) Magneto-Therapy

      In a double-blind, randomized controlled, pilot study, Benedetti and colleagues (2018) examined the efficacy of Bio-Electro-Magnetic-Energy-Regulation (BEMER) magneto-therapy on pain and functional outcome in CRPS-I. These investigators hypothesized that BEMER therapy, based on its declared effects on microcirculation, could be beneficial in the treatment of this condition. This trial included 30 patients with CRPS-I. Patients were divided into 2 groups: a study group, in which the rehabilitation program was combined with BEMER therapy for 10 consecutive days, and a control group, in which the rehabilitation program was combined with a sham BEMER treatment. Outcome measures (VAS pain Hand Grip Strength Disabilities of the Arm, Shoulder, and Hand [DASH] Maryland Foot Score) were taken at the beginning and end of treatment, and at 1 month follow-up. The study demonstrated that the group treated with BEMER combined with rehabilitation yielded better results in the short-term, in terms of pain reduction and functional improvement both at the upper and lower limbs. The authors concluded that findings from this pilot study suggested that BEMER therapy could be used, in combination with traditional rehabilitation programs, for the treatment of CRPS-I. This was a small study (n = 30) with short-term follow-up (1 month) these preliminary findings need to be validated by well-designed studies.

      Ketamine Metabolite (2R,6R)-Hydroxynorketamine

      Kroin and colleagues (2019) noted that ketamine has been shown to reduce chronic pain however, the AEs associated with ketamine makes it challenging for use outside of the peri-operative setting. The ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) has a therapeutic effect in mice models of depression, with minimal side effects. These researchers examined if (2R,6R)-HNK has efficacy in both acute and chronic mouse pain models. Mice were tested in 3 pain models: nerve-injury neuropathic pain, tibia fracture CRPS type-1 (CRPS1) pain, and plantar incision post-operative pain. Once mechanical allodynia had developed, systemic (2R,6R)-HNK or ketamine was administered as a bolus injection and compared with saline control in relieving allodynia. In all 3 models, 10 mg/kg ketamine failed to produce sustained analgesia. In the neuropathic pain model, a single intraperitoneal injection of 10 mg/kg (2R,6R)-HNK elevated von Frey thresholds over a time period of 1 to 24 hours compared with saline (F = 121.6, p < 0.0001), and 3 daily (2R,6R)-HNK injections elevated von Frey thresholds for 3 days compared with saline (F = 33.4, p = 0.0002). In the CRPS1 model, 3 (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 4 days compared with saline (F = 116.1, p < 0.0001). In the post-operative pain model, 3 (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 5 days compared with saline (F = 60.6, p < 0.0001). The authors concluded that the findings of this study showed that (2R,6R)-HNK was superior to ketamine in reducing mechanical allodynia in acute and chronic pain models and suggested it may be a new non-opioid drug for future therapeutic studies.

      Metformin

      Das and colleagues (2020) stated that metformin has previously been shown to decrease mechanical allodynia in mice with neuropathic pain. These researchers examined if treatment with metformin during the first 3 weeks after fracture would produce a long-term decrease in mechanical allodynia and improve a complex behavioral task (burrowing) in a mouse tibia fracture model with signs of CRPS. Mice were allocated into distal tibia fracture or non-fracture groups (n = 12 per group). The fracture was stabilized with intramedullary pinning and external casting for 21 days. Animals were then randomized into 4 groups (n = 6 per group): fracture, metformin treated fracture, saline treated non-fracture, metformin treated and non-fracture, saline treated. Mice received daily intraperitoneal injections of metformin 200 mg/kg or saline between days 14 and 21. After cast removal, von Frey force withdrawal (every 3 days) and burrowing (every 7 days) were tested between 25 and 56 days. Paw width was measured for 14 days after cast removal adenosine monophosphate (AMP)-activated protein kinase down-regulation at 4 weeks after tibia fracture in the dorsal root ganglia was examined by immunohistochemistry for changes in the AMP-activated protein kinase pathway. Metformin injections elevated von Frey thresholds (reduced mechanical allodynia) in CRPS mice versus saline-treated fracture mice between days 25 and 56 (difference of mean area under the curve, 42.5 g·d 95 % CI: 21.0 to 63.9 p < 0.001). Metformin also reversed burrowing deficits compared to saline-treated tibial fracture mice (difference of mean area under the curve, 546 g·d 95 % CI: 68 to 1024 p < 0.022). Paw width (edema) was reduced in metformin-treated fracture mice. After tibia fracture, AMP-activated protein kinase was down-regulated in dorsal root ganglia neurons, and mechanistic target of rapamycin, ribosomal S6 protein, and eukaryotic initiation factor 2α were up-regulated. The authors concluded that the important finding of this study was that early treatment with metformin reduced mechanical allodynia in a CRPS model in mice. They stated that these findings suggested that AMP-activated protein kinase activators may be a viable therapeutic target for the treatment of pain associated with CRPS.

      Mycophenolate

      Goebel and colleagues (2018) noted that current therapies for persistent CRPS are grossly inadequate. With accruing evidence to support an underlying immunological process and anecdotal evidence suggesting potential efficacy of mycophenolate, these researchers examined the feasibility and effectiveness of this treatment in patients with CRPS. They carried out a randomized, open, parallel, proof-of-concept trial. Patients with Budapest research criteria CRPS of greater than 2-year duration and moderate or high pain intensity (NRS score of greater than or equal to 5) were enrolled. Eligible patients were randomized 1:1 to openly receive mycophenolate as add-on treatment, or their usual treatment alone, over 5.5 months. They then switched to the other treatment arm for 5.5 months. The main outcome was patients' average pain intensity recorded over 14 days, between 5.0 and 5.5 months post-randomization, on 11-point (0 to 10) NRS, compared between trial arms. Skin sensitivities and additional outcomes were also assessed. A total of 12 patients were enrolled 9 provided outcomes and were analyzed for the main outcome. Mycophenolate treatment was significantly more effective than control [drug-group mean (SD): pre: 7.4 (1.2) - post: 5.2 (1.3), n = 4, control: pre: 7.7 (1.4) - post: 8.1 (0.9), n = 5 -2.8 (95 % CI: -4.7 to -1.0), p = 0.01, analysis of co-variance]. There were 4 treatment responders (to mycophenolate treatment either before, or after switch), whose initial exquisite skin hyper-sensitivities, function and QOL strongly improved. Side effects including itchiness, skin-cryptitis, increased pain, and increased depression caused 45 % of the subjects to stop taking mycophenolate. The authors concluded that mycophenolate appeared to reduce pain intensity and improve QOL in a subgroup of patients with persistent CRPS. These investigators stated that these findings supported the feasibility of conducting a definite trial to confirm the efficacy and effect size of mycophenolate treatment for persistent CRPS.

      Topical Ketamine

      Durham and colleagues (2018) evaluated the effectiveness and adverse effects of topical ketamine in the treatment of CRPS. Retrospective charts were reviewed of patients 18 years or older diagnosed with CRPS and treated with topical ketamine during the study period of May 2006 to April 2013 in an academic medical center specialty pain clinic. Exclusion criteria consisted of subjects who were treated with topical ketamine for pain syndromes other than CRPS initiated other pain therapies concurrently with topical ketamine had less than 2 documented visits began use of topical ketamine prior to the start of the study period and were under 18 years of age. Subjects with ICD-9 diagnoses codes CRPS-1 or CRPS-2 were identified from encounter-based data and billing records. Data collected for each subject included demographics, description of CRPS, concurrent medications and medical conditions, type of ketamine compound prescribed, duration of therapy, side effects, reasons for discontinuation (if any), and pain scores (numerical pain rating scale 0 to 10). Data were analyzed using descriptive statistics. Institutional Review Board (IRB) approval was obtained prior to initiating the study. A total of 16 subjects met the inclusion/exclusion criteria for the study, 69 % were women with an average age of 46 years (range of 24 to 60). Subjects took an average of 3.7 other pain medications (range of 2 to 8), had an average of 2.7 other co-morbid pain conditions (range of 1 to 5), and 1.6 other co-morbid non-pain conditions (range of 0 to 4) 8 (50 %) reported that their pain had improved, while 7 (44 %) reported a worsening of pain 1 reported no change in pain score. No subjects reported adverse effects. The authors concluded that the use of topical ketamine in the treatment of CRPS showed promise due to the overall limited options available to treat this condition, as well as the favorable safety profile of topical agents. These researchers stated that future prospective controlled studies are needed to demonstrate a clear benefit.

      Combined Dorsal Root Ganglion Stimulation and Dorsal Column Spinal Cord Stimulation

      Ghosh and Gungor (2020) examined the use of combined DRG stimulation and SCS for the treatment of CRPS. This trial included 4 patients with severe CRPS who had all been implanted with a spinal cord stimulator (t-SCS). While all these patients had positive results from their t-SCS, they all had areas which lacked coverage, giving them incomplete pain relief. These patients also underwent successful trial and implantation of DRG stimulator (DRG-S). All 4 patients reported further improvement in their residual pain and function with DRG-S (greater than 60 %), and even superior pain relief (greater than 80 %) with concurrent use of DRG-S and t-SCS. All patients had a diagnosis of lower extremity CRPS-1. After DRG-S implantation, multiple attempts were made in each patient to use DRG-S alone by temporarily turning off the t-SCS. However, in each attempt, all patients consistently reported superior pain relief and improvement in function with the concurrent use of DRG-S and t-SCS, as compared to DRG-S alone. The average numeric rating scale pain score decreased from approximately 7 in the regions not covered by t-SCS to 3 after DRG-S implantation, and to 1.25 with concurrent use of DRG-S and t-SCS. The authors concluded that combined use of DRG-S and t-SCS provided significant improvement in pain and function as compared to using either device alone suggesting the potential that combination therapy with DRG-S and t-SCS may be beneficial in patients with CRPS. Moreover, these researchers stated that further prospective studies are needed to evaluate this concept.

      Combined Transcranial Direct Current Stimulation and Transcutaneous Electrical Nerve Stimulation

      Houde and colleagues (2020) noted that CRPS is a rare neuropathic pain condition characterized by sensory, motor and autonomic alterations. Previous investigations have shown that transcranial direct current stimulation (tDCS) and transcutaneous electrical nerve stimulation (TENS) can alleviate pain in various populations, and that a combination of these treatments could provide greater hypoalgesic effects. In a single-case study, these researchers described the effect of tDCS and TENS treatment on pain intensity and unpleasantness in a patient suffering from chronic CRPS. The patient was a 37-year old woman, suffering from left lower limb CRPS (type I) for more than 5 years. Despite medication (pregabalin, tapentadol, duloxetine), rehabilitation treatments (sensorimotor retraining, graded motor imagery) and SCS, the subject reported moderate-to-severe pain. Treatments of tDCS alone (performed with SCS turned off during tDCS application, 1 session/day, for 5 consecutive days) did not significantly decrease pain. Combining tDCS with TENS (SCS temporarily turned off during tDCS, 1 session/day, for 5 consecutive days) slightly reduced pain intensity and unpleasantness. The authors concluded that these findings suggested that combining tDCS and TENS could be a therapeutic strategy worth investigating further to relieve pain in chronic CRPS patients. These researchers stated that future studies should examine the efficacy of combined tDCS and TENS treatments in CRPS patients, and other chronic pain conditions, with special attention to the cumulative and long-term effects and its effect on function and QOL.

      Exergame Therapy

      Storz and colleagues (2020) stated that CRPS is a disease of the limbs composed of various disorders and defined by the cardinal symptom of pain. So-called exergames with a combination of physical activity and fun are increasingly being offered as part of treatment. Exergame therapy could also provide CRPS patients with repetitive training, reward and motivation. In a feasibility study, a total of 10 adults with CRPS of the hand (50 % acute) received a 30-min therapy session using MindMotion™GO, which is a software that enables control of the integrated games through visual feedback. Outcomes were the subjectively perceived work-load (National Aeronautics and Space Administration-task load index, NASA-TLX), user-friendliness (system usability scale, SUS) and pain (NRS). Subjects rated the average work-load as appropriate with a total score of 50.9 points (SD ± 18.13). The user-friendliness of the system was judged to be acceptable with an average total score of 89.5 ± 7.53 points. There were no significant changes in pain intensity after the exergames. The subgroup analysis (acute versus chronic) showed differences in the assessment of the individual dimensions of the work-load. The authors concluded that the use of exergame therapy proved to be a suitable tool for rehabilitation of the hand in adult CRPS patients. Moreover, these researchers stated that whether exergame therapy represents an effective rehabilitation strategy should be examined by means of functional and activity-related target criteria in a representative sample in a RCT.

      Sanexas (Electroanalgesia)

      The Sanexas electric cell signaling system uses electronic signal energy waves produced by an ultra-high digital frequency generator. The system produces both low-frequency and middle-frequency signals, and also used amplitude modulated (AM) and frequency modulated (FM) signaling. These therapeutic energy waves are intended to stimulate the body on a cellular level without causing discomfort. During a treatment session, the Sanexas system automatically changes to simultaneously deliver AM and FM electric cell signal energy. There is a lack of peer-reviewed published data on the effectiveness of the Sanexas system. .An UpToDate review on “Complex regional pain syndrome in adults: Treatment, prognosis, and prevention” (Abdi, 2020) does not mention electroanalgesia as a therapeutic option.

      Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation

      In a case-report, Fritz and colleagues (2019) presented an application of percutaneous peripheral nerve stimulation (PNS) to the left ulnar nerve to treat a patient with CRPS1 following a crush injury to the left 5th digit. Conventional treatment had failed to ameliorate the patient's condition. After a successful 7-day trial with an ulnar peripheral nerve catheter, which followed an unsuccessful capsulectomy of the metacarpophalangeal and proximal interphalangeal joints of the left 5th digit with tenolysis of the flexor tendons, the patient underwent an uneventful implantation of a percutaneous peripheral nerve stimulator parallel with the trajectory of the left ulnar nerve just distal to the ulnar tunnel. Two weeks after implantation of the percutaneous peripheral nerve stimulator, the patient reported a reduction in the pain, with the intensity score coming down from 7 out of 10 to 0 to 1 out of 10 on the NRS. The patient was able to initiate pain-free active motion of her left 5th digit. At the 3-month follow-up consultation, the patient reported maintenance of the reduction of pain in her left upper extremity with the implanted percutaneous peripheral nerve stimulator, as well as improved performance in her daily activities. The authors concluded that despite the success achieved in this particular case, further clinical series involving larger numbers of patients are needed to examine the definitive role of percutaneous PNS for the treatment of neuropathic pain of the upper and lower extremities, which has been previously unresponsive to medical and/or surgical treatment.


      A disorder of unknown aetiology that is characterized by widespread pain, abnormal pain processing, sleep disturbance, fatigue and often psychological distress.

      Pain caused by a lesion or a disease of the somatosensory nervous system.

      Chronic constrictive injury model

      An animal model of mononeuropathic pain in rodents resulting from ligation of the sciatic nerve, which induces a painful syndrome analogous to that observed in humans. Chronic constrictive injury models may differ according to the location and the tightness of the ligation along the sciatic nerve.

      Rats that mimic the symptoms induced by nerve injury in humans. Symptoms are restricted to the area innervated by the injured nerve.

      A method of determining drug synergy. The theoretical additive ED50 value (the half-maximal effective dose) is estimated from the dose–response curves of each drug administered individually. This theoretical ED50 value is compared with the experimental ED50 value. If a statistically significant difference is observed, synergy is present.