CRPS/RSD Drugs and Treatmentstwirling vial

    Some of the medications and procedures commonly used to treat CRPS and other types of chronic pain have special cautions and considerations that must be known and carefully reviewed by people considering these drugs or treatment protocols. With medications, the problems can range from histamine-type allergic reactions to unintentional life-threatening accumulation of drug and/or metabolites in the body. The non-drug procedures (spinal cord stimulation, etc.) have special sets of concerns, often associated with their invasive nature. These drugs and treatments are listed and discussed as the need arises, suggestions are made, or when it becomes known that serious issues exist.

Are you looking for information on a specific drug or family of drugs that weren't developed specifically for CRPS? If so, you may want to check the Drug Information page as well as this one.

    Medscape has published an interactive site showing, state by state, opiate prescribing and other laws regarding controlled substances. If you don't know about the Controlled Substance Act (CSA in Wikipedia), it's not a bad idea to become familiar with the basic idea.

Animations of Many RSD Treatments

     Many procedures and therapies with scary names abound in RSD treatment. The Advanced Pain Institute has produced a very nice series of nearly 30 narrated animations that show, step-by-step, exactly what's involved in procedures from Caudal Steroid Injections to Spinal Cord Stimulator Implants. Highly recommended!

    All of the references in the table below are delivered as PDF files.

NOTE: For nearly all topics below, a much larger selection of articles appears in the site's Library! Take a look!

Cannabinoids

So far, 20 states have Medical Marijuana laws in place, with varying degrees of interference from the DEA. Those who have used it universally endorse its effectiveness for the worst symptoms of CRPS.
NOTE: Many of these papers are quite technical, but many aren't at all.


1. Cannabinoid CB2 Receptors Contribute to Upregulation of β-endorphin
2. Experiences with the Synthetic Cannabinoid Nabilone in Chronic Noncancer Pain
3. Cannabinoid–Opioid Interaction in Chronic Pain
4. Effects of cannabinoids on neuropeptide γ- and β-endorphin expression
5. Endocannabinoids: endogenous cannabinoid receptor ligands with neuro-modulatory action
6. There is also a great section called Chronic Pain and Medical Marijuana, on the site Americans for Safe Access (ASA). ASA is "the largest organization of patients, medical professionals, scientists and concerned citizens promoting safe and legal access to cannabis."
7. Predictive model accuracy in estimating last Δ9-THC intake from plasma and whole blood cannabinoid concentrations in chronic daily cannabis smokers administered subchronic oral THC
8. Nice graphic (jpg) showing all of cannabis' medicinal actions as a function of the cannabinoid receptor.
9. Top 10 Cannabis Studies the Government Wished it Had Never Funded
10. International Association for Cannabis as Medicine
11. Journals about Cannabis' Medicinal Effects:
Medical Cannabis Journal
Cannabis Health Journal
The Los Angeles Journal for Education on Medical Marijuana
Medical Marijuana Business Daily
Cannabinoids - The Journal of the International Association for Cannabinoid Medicines
12. Medical Marijuana Doctors "Marijuana Doctors 411 is composed of specialized cannabis connoisseurs or “cannaseurs” with real insight within the Medical Marijuana industry and cannabis as a whole. Originally founded in September 2010, the MD411 team has worked on filtering out fluffed up and vague information pieces in order to provide the “Raw Truth” in terms of cannabis and the Medicinal Marijuana industry." [emphases in original]

Another significant benefit to THC in the context of treating CRPS is that it acts synergistically with opioids, boosting their strength and even lessening the development of tolerance. This short section covers papers that address this phenomenon.

13. Antinociceptive Synergy between Δ9-Tetrahydrocannabinol and Opioids after Oral Administration
14. Efficacy of Dronabinol as an Adjuvant Treatment for Chronic Pain Patients on Opioid Therapy
15. Low dose combination of morphine and Δ9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors
16. Synergy between Δ9-tetrahydrocannabinol and morphine in the arthritic rat
17. Time course of the enhancement and restoration of the analgesic efficacy of codeine and morphine by Δ9-tetrahydrocannabinol
18. Synergistic affective analgesic interaction between Δ9-tetrahydrocannabinol and morphine
19. Enhancement of transdermal fentanyl and buprenorphine antinociception by transdermal Δ9-tetrahydrocannabinol

Recent news items about the benefits/dangers of using medical marijuana:

Striking a Nerve: Bungling the Cannabis Story an editorial by MedpageToday, one of the most authoritative sources of accurate medical information on the web, which shows the slanted coverage given stories of negative effects of cannabis.

Bisphosphonates (anti-osteoporosis drugs)

Several drugs which are usually prescribed to treat osteoporosis have recently been used to treat CRPS. In addition to slowing or stopping bone demineralization and subsequent thinning and loss of bone density (osteopenia, osteoporosis), bisphosphonates apparently inhibit the release of inflammatory cytokines, which have been implicated as a mediator and propagator of CRPS pain.

1. Bisphosphonates: Focus on Inflammation and Bone Loss
2. CRPS and Osteoporosis nice 12-pg pamphlet from the National Osteoporosis Society
3. Effect of Immunomodulating Medications in Complex Regional Pain Syndrome - A Systematic Review
4. Efficacy of Pamidronate in Complex Regional Pain Syndrome Type I
5. An Open-label Pilot Trial of Ibandronate for Complex Regional Pain Syndrome
6. Role of Alendronate in Therapy for Posttraumatic Complex Regional Pain Syndrome Type I of the Lower Extremity
7. Role of Biphosphonates and Lymphatic Drainage Type Leduc in the Complex Regional Pain Syndrome (Shoulder– Hand Syndrome)
8. The roles of the sympathetic nervous system in osteoporotic diseases: A review of experimental and clinical studies
9. The successful use of pamidronate in an 11-year-old girl with complex regional pain syndrome: Response to treatment demonstrated by serial peripheral quantitative computerized tomographic scans
10. Treatment of Chronic Mechanical Spinal Pain with Intravenous Pamidronate: A Review of Medical Records
11. Treatment of Reflex Sympathetic Dystrophy with Pamidronate: 29 cases

12. Bisphosphonates for pain relief in reflex sympathetic dystrophy?


Very recently, one of the bisphosphonates (neridronate) has shown powerful and unanticipated activity against CRPS1. This activity was observed in a small study (#13) last year, so this year a study involving 82 patients was carried out (#14), and one year following the study's end, no patient has any CRPS symptom of any kind.

Currently, a very large Phase III trial with neridronate is underway in the US. Not many details are currently known, but as of late July 2015 they were still looking for additional recruits for the study. See the first page in this site for the details and to see if you might qualify.

13. Treatment of complex regional pain syndrome type I with neridronate: a randomized, double-blind, placebo-controlled study
14. Clinical development of neridronate: potential for new applications
15. Efficacy of memantine in the treatment of fibromyalgia: a double-blind randomised controlled trial with 6-month follow-up

Hyperbaric Oxygen Therapy (HBO or HBOT)

Hyperbaric oxygen therapy (HBOT) involves breathing pure oxygen in a pressurized chamber or room. Conditions treated with hyperbaric oxygen therapy include serious infections, bubbles of air in your blood vessels (can happen during a scuba dive where ascent was too rapid, informally called "the bends"), and wounds that can't heal as a result of diabetes, radiation injury, or CRPS/RSD.

1. Hyperbaric oxygen therapy from the Mayo Clinic
2. Hyperbaric Oxygen Therapy, an Overview a great summary from an HBO physician, with many links to studies, bibliographies, etc.
3. Hyperbaric Oxygen Therapy typically excellent summary from MedLine
4. Undersea and Hyperbaric Medical Society
5. Hyperbaric Medicine from Wikipedia
6. Effectiveness of Hyperbaric Oxygen Therapy in the Treatment of Complex Regional Pain Syndrome
7. Tissue hypoxia in complex regional pain syndrome
8. Hyperbaric Oxygen Induces Late Neuroplasticity in Post Stroke Patients - Randomized, Prospective Trial
9. Hyperbaric Oxygenation Therapy Alleviates Chronic Constrictive Injury–Induced Neuropathic Pain

 

Ketamine and other NMDA Receptor Antagonists

Ketamine is a potent anesthetic with a history of abuse; it can induce psychotic states reminiscent of those seen with phencyclidine (PCP). In fact, the structures of the two molecules are extremely similar. It's also a powerful antagonist of the NMDA (N-Methyl-D-Aspartate) receptor with a likely role in the development of central sensitization. It is also, at this time, the most promising chemotherapeutic agent against CRPS/RSD that has yet been discovered, with the possible exception of the bis-phosphonates. However, we have far more experience with ketamine than with the other drug class.

1. Efficacy of Ketamine, esp. in cases of refractory CRPS
2. Ketamine-Induced Pain Relief from Chronic Pain
3. Effect of Ketamine on Endogenous Pain Modulation in Healthy Volunteers
4. Ketamine and Chronic Pain - Going the Distance
5. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: A double-blind placebo controlled study
6. An observational study on the effect of S-(+)-ketamine on chronic pain versus experimental acute pain in CRPS type 1 patients
7. The Dose-Dependent Effect of S-(+)-Ketamine on Cardiac Output
8. Influence of Ketamine on the Analgesic Efficacy of the Agonist-Antagonist Opioids
9. Efficacy and Safety of Ketamine in Patients with Complex Regional Pain Syndrome - A Systematic Review
10. Characterization of the stereoselective biotransformation of ketamine to norketamine via determination of their enantiomers in equine plasma by capillary electrophoresis
11. Ketamine Infusion
12. New Culprits in Chronic Pain - a great article in Scientific American that explains the role of glial structures in pain. Excellent color graphics and lack of overly technical terms make this article truly enjoyable to read!
13. Efficacy of Outpatient Ketamine Infusions in Refractory Chronic Pain Syndromes: A 5-Year Retrospective Analysis
14. Advances in Translational Neuropathic Research: Example of Enantioselective Pharmacokinetic–Pharmaco--dynamic Modeling of Ketamine-induced Pain Relief in Complex Regional Pain Syndrome
15. Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine
16. An observational study on the effect of S-(+)-ketamine on chronic pain versus experimental acute pain in CRPS type 1 patients
17. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: A double-blind placebo controlled study
18. Population pharmacokinetic–pharmacodynamic modeling of ketamine-induced pain relief of chronic pain
19. With Neurofibromatosis Type 1 and Glomus Tumor-Associated Complex Regional Pain Syndrome Oral Ketamine in the Palliative Care Setting: A Review of the Literature and Case Report of a Patient
20. Prolonged ketamine infusion as a therapy for complex regional pain syndrome: synergism with antagonism?

NOTE: There are dozens of articles on ketamine in the Library.

Note added 08/29/2013 - The journal CNS Neuroscience & Therapeutics devoted its June 2013 issue to review articles concerning research on ketamine; 10 of these articles are in the Library's Ketamine section.

Note added 10/03/2013 - I just ran across a paper called "Ketamine and Addiction", to which I want to call attention. The author attempts to make a case for the addiction liability of ketamine, based totally on anatomical features on brain fMRI. It's very revealing to see how a researcher can make a case for something, and actually get it accepted, without a single reference to a study involving humans becoming addicted to ketamine. Check it out - this is the kind of article that very good peer reviewing is supposed to reject; occasionally a study of questionable design is accepted.


Other drugs also exhibit similar antagonistic activity, and one has recently shown much promise as a new agent for CRPS. Called memantine (Namenda®), it shows the same NMDAR antagonism, but without the distressing side-effects, especially the psychological ones (dissociation, agitation, hallucinations). It's a drug that was developed (and is FDA-approved) for osteoporosis/osteopenia. Memantine's efficacy against CRPS was completely unanticipated, and, as so often happens in medicinal chemistry, was serendipitously observed in a population of osteoporosis patients who also happened to have CRPS. Here are but a few articles on this discovery:

There are many more articles (nearly 30) on ketamine and other NMDAR antagonists in the Library.

Methadone Metabolism

Methadone, a staple of opioids used for chronic pain, including CRPS, is subject to highly variable metabolism rates due to enzyme mixtures, which are genetically determined and unique to each person and can cause problems with compliance urinalyses. Based on the number of receptor sites expressed, a person falls into one of four categories, from "slow metabolizer" to "ultra-fast metabolizer". Those in the "slow" category might take several days to show no methadone, while the "ultra-fast" folks (like me) can take a 10mg tablet of methadone, and, an hour later, show no trace of the drug in the urine.

Genetic screening can tell, quickly and cheaply, into which category you fall. If you take methadone, I strongly urge you to do this. If you happen to be in the ultra-fast category, you'll want to be able to document this for any pain management physician who uses urinalysis to verify that you're taking the prescribed drugs (instead of selling them or something equally illegal). In fact, I did the research and got the test after I'd showed up with clean urine for three docs in a row. I guarantee that knowing my status beforehand would have simplified my life greatly at those times!

1. Methadone-Drug Interactions
2. Stereoselective Methadone Metabolism
3. Ultrarapid Drug Metabolism: PCR-Based Detection of CYP2D6 Gene Duplication
4. Interindividual Variability of Clinical Methadone Pharmacokinetics
5. Assoc. of CYP2D6 ultrarapid metabolizer genotype with poor patient satisfaction regarding methadone maintenance Tx

 

Mirror Therapy

Mirror therapy began with phantom limb Tx, where a box with a mirror bisecting it within allowed the patient to "see" two arms when only one is there. This has been extended to CRPS treatment.

1. Mirror Visual Feedback Therapy and Its Application for the Tx of CRPS
2. Derangement of body representation in CRPS: report of a case treated with mirror and prisms
3. Mirror Therapy for Chronic CRPS Type 1 and Stroke
4. Mirror Therapy in CRPS 1 of the Upper Limb in Stroke Patients

 

Nerve Ablation (cutting, burning, radiofrequency (RF), etc.)

Many years ago, cutting the nerve(s) seemed to make sense, but it's mostly been replaced with more reversible and selective techniques. Still, sympathectomies have their supporters in the medical community, as well as serious detractors.

1. Evidence-Based Interventional Pain Medicine 16. CRPS
2. Efficacy and Safety of Radiofrequency Lesioning of the Dorsal Root Ganglion/ Segmental Nerve for Lumbar Radicular Pain
3. Surgical pelvic neuroablation for chronic pelvic pain: a systematic review
4. Radiofrequency Ablation of Cancer

 

Opana®, Exalgo® (hydromorphone)

Oxymorphone is much stronger than oxycodone; patients must be very careful to avoid overdosing and/or interactions with other opioids or sedatives, tranquilizers, hypnotics, etc.

1. Highlights of Prescribing Information
2. Prescribing Data for Opana injection

 

Opioids in General

Tolerance, compliance, abuse, addiction, withdrawal, etc.

1. A Clinical Guide to Opioid Analgesia; 135 pages
2. Sample Opioid Contract
3. Use of Opioid Analgesics for the Treatment of Noncancer Chronic Pain
4. Role of SR Opioids in Treating Chronic Pain (SR = sustained release)
5. Thoughts on Tolerance, Hyperalgesia, and Short-Acting Opioids
6. Safely Discontinuing Opioid Analgesics
7. Understanding Your Pain - Taking Oral Opioid Analgesics
8. Alternatives to the Oral Delivery of Opioids
9. Routes of Opioid Analgesic Therapy in the Management of Cancer Pain
10. The Opium Analgesics; 91 pages

In 2012, the journal Pain Physician devoted an entire issue to opioids and their use. All 19 chapters are now available here:

Chap. No.
Chapter (& link)
Length
1
8 pp
2
8 pp
3
26 pp
4
18 pp
5
16 pp
6
66 pp
7
50 pp
8
30 pp
9
8 pp
10
20 pp
11
16 pp
12
10 pp
13
12 pp
14
12 pp
15
14 pp
16
10 pp
17
8 pp
18
14 pp
19
6 pp

NOTE: There are dozens of articles on opioids in the Library.

Opioid Treatment Guidelines

Pain Exposure Physical Therapy (PEPT)

Scrambler/Calmare® Therapy

Neural Stimulation (except SCS)

Following the success of spinal cord stimulation (SCS), additional methods for neural stimulation have been investigated, and include a variety of approaches. The most exciting and potentially revolutionary route, currently, is direct brain stimulation, using either electrical or magnetic energy to affect the brain's nerve cells.

1. Computer-based model of epidural motor cortex stimulation: Effects of electrode position and geometry on activation of cortical neurons
2. Intraoperative neurophysiologic mapping of the central cortical region for epidural electrode placement in the treatment of neuropathic pain by motor cortex stimulation
3. Methods of therapeutic cortical stimulation
4. Modulation of motor cortex excitability by different levels of whole-hand afferent electrical stimulation
5. Motor cortex stimulation for central and neuropathic pain: current status (review)
6. Noninvasive brain stimulation with transcranial magnetic or direct current stimulation (TMS/tDCS)—From insights into human memory to therapy of its dysfunction
7. Polarity of cortical electrical stimulation differentially affects neuronal activity of deep and superficial layers of rat motor cortex
8. Principles of therapeutic use of transcranial and epidural cortical stimulation (invited review)
9. Treatment of chronic neuropathic pain by motor cortex stimulation: Results of a bicentric controlled crossover trial
10. The use of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to relieve pain

Spinal Cord Stimulation (SCS)

Therapeutic Injections for Pain Management

Systemic toxic reactions to LAs can result from high blood levels of the drug due to accidental intravenous (IV) infusion. This section covers the many types of neural blocks done in treating CRPS.

1. Adverse Effects and Complications of Neural Blockade
2. Cervical spinal nerve blocks
3. Sympathetic Nervous System Blockade
4. Types of therapeutic injections

Palmitoylethanolamide (PEA)

Palmitoylethanolamide (PEA) is an endogenous (occurs naturally in the body) compound in a class called lipid mediators, and is known to exert antinociceptive effects, as well as prevent neurotoxicity and neurodegeneration. It also inhibits peripheral inflammation and mast cell degeneration, and can modulate microphage response. It does this by activating a special receptor called PPAR-α.

1. Palmitoylethanolamide Is a Disease-Modifying Agent in Peripheral Neuropathy: Pain Relief and Neuroprotection Share a PPAR-Alpha-Mediated Mechanism
2. Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide
3. Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models
4. The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB1, TRPV1 and PPARc receptors and neurotrophic factors
5. Palmitoylethanolamide in the Treatment of Chronic Pain Caused by Different Etiopathogenesis
6. ‘Entourage’ effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors
7. Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-αagonist and effective nutraceutical
8. N-(4-Methoxy-2-nitrophenyl)hexadecanamide, a palmitoylethanolamide analogue, reduces formalin-induced nociception
9. Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats
10. New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide
11. Molecular evidence for the involvement of PPAR-δ and PPAR-γ in anti-inflammatory and neuroprotective activities of palmitoylethanolamide after spinal cord trauma
12. Full Inhibition of Spinal FAAH Leads to TRPV1-Mediated Analgesic Effects in Neuropathic Rats and Possible Lipoxygenase-Mediated Remodeling of Anandamide Metabolism

Vitamin D

Vitamin C

Vitamin C has been utilized in a number of strategies to avoid the development of CRPS following (and occasionally before) an event known to cause CRPS in some individuals. The two most common causes of CRPS, respectively, are surgery and fractures.

1. Efficacy and Safety of High-dose Vitamin C on Complex Regional Pain Syndrome in Extremity Trauma and Surgery - Systematic Review and Meta-Analysis
2. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial
3. Can Vitamin C Prevent Complex Regional Pain Syndrome in Patients with Wrist Fractures? [letter in response to the paper in #2]
4. P.E. Zollinger, W.E. Tuinebreijer, R.S. Breederveld, and R.W. Kreis reply [these were the authors of paper #2, responding to the letter in #3]
5. Can Vitamin C Prevent Complex Regional Pain Syndrome in Patients with Wrist Fractures? [another letter in response to the paper in #2, again followed by the authors' reply]
6. IS MIGRAINE A COMPLEX REGIONAL PAIN SYNDROME OF THE BRAIN? MIGRAINE PROPHYLAXIS WITH VITAMIN C?
7. Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery
8. Letter to Editor about Above Article
9. Clinical outcome of cementless semi-constrained trapeziometacarpal arthroplasty, and possible effect of Vitamin C on the occurrence of complex regional pain syndrome
10. Complex Regional Pain Syndrome of the Upper Extremity
11. Update on the pathogenesis of complex regional pain syndrome: Role of oxidative stress
12. ...PREVENTING COMPLEX REGIONAL PAIN SYNDROME
13. Anti-inflammatory treatment of Complex Regional Pain Syndrome
14. Evidence based guidelines for complex regional pain syndrome type 1

Complementary and Alternative Medicine

The phrase "Complementary and Alternative Medicine" (CAM) is most commonly associated with therapeutic techniques or treatments that are outside the realm of typical Western medicine, although they might be used in other countries for medical applications. Some CAM techniques have histories stretching back many thousands of years, such as massage therapy, herbs, and acupuncture.

In the early 1990s, the National Center for Complementary and Alternative Medicine (NCCAM) was founded as part of the National Institutes of Health (NIH). According to its web site, "NCCAM is dedicated to exploring complementary and alternative healing practices in the context of rigorous science, training complementary and alternative medicine (CAM) researchers, and disseminating authoritative information to the public and professionals."

Intrathecal Drugs and Drug Pumps

Intrathecal delivery of medications involves the direct introduction of drugs into the spinal column, i.e., the cerebrospinal fluid (CSF). Although obviously quite invasive, the technique embodies several important advantages, especially for those who are running out of options to achieve satisfactory pain control:

  • The drug is introduced directly into the central nervous system, without having to deal with metabolism, protein binding, and other sites of loss associated with intravenous or oral delivery.
  • Because of the direct introduction into the CNS, only a fraction of normal drug doses are needed. The amounts injected are typically measured in micrograms, rather than milligrams.
  • Because the severity of side-effects depends on the quantity of drug used, intrathecal drugs involve virtually no side-effects whatsoever, including constipation, sedation, nausea, tolerance, addiction, etc.
  • The lack of toxic side-effects means that there is virtually no limit to the amount of drug that can be used. For terminal patients whose tolerance is so high that even IV morphine is of little help, intrathecal opioids can make the remainder of their lives relatively comfortable.

Most narcotics can be introduced intrathecally, but many are being developed specifically for this application. Recently, the first drug was approved by the FDA specifically for chronic neuropathic pain, called Prialt® (ziconotide), which was first isolated from the toxins that a small Ecuadorean tree frog secretes from its skin to avoid being eaten.

1. Administering Ziconotide and Monitoring Patients Treated with Ziconotide: Expert Opinions
2. Bolus Intrathecal Injection of Ziconotide (Prialt®) to Evaluate the Option of Continuous Administration via an Implanted Intrathecal Drug Delivery (ITDD) System: A Pilot Study
3. Intrathecal Ziconotide: A Review of Its Use in Patients with Chronic Pain Refractory to Other Systemic or Intrathecal Analgesics
4. Intrathecal Ziconotide for Refractory Chronic Pain
5. Overview of Drug Pump technology from the Mayfield Clinic - excellent
6. Summary of intrathecal pumps from Medtronic, Inc., who manufactures most of the needed hardware
7. Also from Medtronic, an article outlining the benefits and risks from intrathecal drug therapy
8. From Spinehealth.com, a very good video on implanting and using intrathecal drugs