CRPS Bugle February 2013

pills_2134870bHere are some recent papers looking at common drugs used for neuropathic pain. Drugs play a role in the treatment of complex regional pain syndrome as part of a comprehensive programme that targets the pain mechanisms and the physical, cognitive and emotional aspects of the condition. Pain is multidimensional, individual and subjective and must be addressed as such.

RS – Specialist Pain Physio Clinics in London for complex and persisting pain

Am J Med. 2013 Mar;126(3 Suppl 1):S3-S11. doi: 10.1016/j.amjmed.2012.11.011.

Opioids for chronic pain: new evidence, new strategies, safe prescribing.

de Leon-Casasola OA.


Departments of Anesthesiology and Medicine, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA; and Division of Pain Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. Electronic address:


In the United States, the prevalence and burden of chronic pain is large and still growing. Older adults (aged ≥65 years) make up a large portion of the population with chronic pain, and their presentation, diagnosis, and treatment tends to be more complicated because of age-related physiological changes and comorbidities. Guidelines on treating patients with severe back pain recommend opioids as an option for those who do not find adequate pain relief from acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). For older adult patients at higher risk for NSAID-related adverse effects, such as those who have gastrointestinal or cardiovascular disease, diabetes mellitus, or who are taking low-dose aspirin, opioids are recommended instead. Opioids may also be an appropriate option for patients with neuropathic pain who have not achieved adequate analgesia from maximum doses of first- and second-line antineuropathic agents. Still, opioids are not appropriate for all patients; rather, a differential diagnosis, consideration of other comorbidities, and the potential for opioid-related adverse effects and substance abuse are required to confirm the value of opioid treatment for each individual. For nonresponders to opioid therapy, opioid rotation should be considered before discontinuation is pursued


Arch Pharm Res. 2013 Feb 24. [Epub ahead of print]

Implications and mechanism of action of gabapentin in neuropathic pain.

Kukkar A, Bali A, Singh N, Jaggi AS.


Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India.


Gabapentin is an anti-epileptic agent but now it is also recommended as first line agent in neuropathic pain, particularly in diabetic neuropathy and post herpetic neuralgia. α2δ-1, an auxillary subunit of voltage gated calcium channels, has been documented as its main target and its specific binding to this subunit is described to produce different actions responsible for pain attenuation. The binding to α2δ-1 subunits inhibits nerve injury-induced trafficking of α1 pore forming units of calcium channels (particularly N-type) from cytoplasm to plasma membrane (membrane trafficking) of pre-synaptic terminals of dorsal root ganglion (DRG) neurons and dorsal horn neurons. Furthermore, the axoplasmic transport of α2δ-1 subunits from DRG to dorsal horns neurons in the form of anterograde trafficking is also inhibited in response to gabapentin administration. Gabapentin has also been shown to induce modulate other targets including transient receptor potential channels, NMDA receptors, protein kinase C and inflammatory cytokines. It may also act on supra-spinal region to stimulate noradrenaline mediated descending inhibition, which contributes to its anti-hypersensitivity action in neuropathic pain.


Br J Clin Pharmacol. 2013 Feb 21. doi: 10.1111/bcp.12094. [Epub ahead of print]

Ketamine for Chronic Pain: Risks and Benefits.

Niesters M, Martini C, Dahan A.


Department of Anesthesiology, Leiden University Medical Center, 2300, RC, Leiden, The Netherlands.


The anesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low-dose ketamine produces strong analgesia in neuropathic pain states, presumably by inhibition of the N-methyl-D-aspartate receptor although other mechanisms are possibly involved, including enhancement of descending inhibition and anti-inflammatory effects at central sites. Current data on short-term infusions indicate that ketamine produces potent analgesia during administration only, while three studies on the effect of prolonged infusion (10-14 days) show long-term analgesic effects up to 3 months following infusion. Ketamine’s side-effects noted in clinical studies include psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence, cardiovascular stimulation, and in a minority of patients hepatoxicity. The recreational use of ketamine is increasing and comes with a variety of additional risks ranging from bladder and renal complications to persistent psychotypical behaviour and memory defects. Blind extrapolation of these risks to clinical patients is difficult, because of the variable, high and recurrent exposure to the drug in ketamine abusers and the high frequency of abuse of other illicit substances in this population. In clinical settings, ketamine is well tolerated, especially when benzodiazepines are used to tame the psychotropic side-effects. Irrespective, close monitoring of patients receiving ketamine is mandatory, particularly aimed at CNS, hemodynamic, renal and hepatic symptoms as well as abuse. Further research is required to assess whether the benefits outweigh the risks and costs. Until definite proof is obtained ketamine administration should be restricted to patients with therapy-resistant severe neuropathic pain.


Cochrane Database Syst Rev. 2012 Dec 12;12:CD008242. doi: 10.1002/14651858.CD008242.pub2.

Amitriptyline for neuropathic pain and fibromyalgia in adults.

Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ.


Pain Research and Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.



Amitriptyline is a tricyclic antidepressant that is widely used to treat chronic neuropathic pain (pain due to nerve damage) and fibromyalgia, and is recommended in many guidelines. These types of pain can be treated with antidepressant drugs in doses below those at which the drugs act as antidepressants.


To assess the analgesic efficacy of amitriptyline for chronic neuropathic pain and fibromyalgia.To assess the adverse events associated with the clinical use of amitriptyline for chronic neuropathic pain and fibromyalgia.


We searched CENTRAL, MEDLINE, and EMBASE to September 2012, together with reference lists of retrieved papers, previous systematic reviews, and other reviews; we also used our own handsearched database for older studies.


We included randomised, double-blind studies of at least four weeks’ duration comparing amitriptyline with placebo or another active treatment in chronic neuropathic pain or fibromyalgia.


We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently. We performed analysis using two tiers of evidence. The first tier used data meeting current best standards, where studies reported the outcome of at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) or other imputation method for dropouts, reported an intention-to-treat (ITT) analysis, lasted 8 to 12 weeks or longer, had a parallel-group design, and where there were at least 200 participants in the comparison. The second tier used data that failed to meet this standard and were therefore subject to potential bias.


Twenty-one studies (1437 participants) were included; they individually involved between 15 and 235 participants, only four involved over 100 participants, and the median study size was 44 participants. The median duration was six weeks. Ten studies had a cross-over design. Doses of amitriptyline were generally between 25 mg and 125 mg, and dose escalation was common.There was no top-tier evidence for amitriptyline in treating neuropathic pain or fibromyalgia.Second-tier evidence indicated no evidence of effect in cancer-related neuropathic pain or HIV-related neuropathic pain, but some evidence of effect in painful diabetic neuropathy (PDN), mixed neuropathic pain, and fibromyalgia. Combining the classic neuropathic pain conditions of PDN, postherpetic neuralgia (PHN) and post-stroke pain with fibromyalgia for second-tier evidence, in eight studies and 687 participants, there was a statistically significant benefit (risk ratio (RR) 2.3, 95% confidence interval (CI) 1.8 to 3.1) with a number needed to treat (NNT) of 4.6 (3.6 to 6.6). The analysis showed that even using this potentially biased data, only about 38% of participants benefited with amitriptyline and 16% with placebo; most participants did not get adequate pain relief. Potential benefits of amitriptyline were supported by a lower rate of lack of efficacy withdrawals; 8/153 (5%) withdrew because of lack of efficacy with amitriptyline and 14/119 (12%) with placebo.More participants experienced at least one adverse event; 64% of participants taking amitriptyline and 40% taking placebo. The RR was 1.5 (95% CI 1.4 to 1.7) and the number needed to treat to harm was 4.1 (95% CI 3.2 to 5.7). Adverse event and all-cause withdrawals were not different.


Amitriptyline has been a first-line treatment for neuropathic pain for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many patients with neuropathic pain or fibromyalgia. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline should continue to be used as part of the treatment of neuropathic pain or fibromyalgia, but only a minority of patients will achieve satisfactory pain relief. Limited information suggests that failure with one antidepressant does not mean failure with all.It is unlikely that any large randomised trials of amitriptyline will be conducted in specific neuropathic pain conditions or in fibromyalgia to prove efficacy.


4 thoughts on “CRPS Bugle February 2013

  1. I would be interested to know info on treatment of CRPS and drugs used for children. I have a 10 yr old on amytriptylene 30 mg/day and would lke to know if anyone has experienced efficency/side effects.She has been on for over a year now.
    I have visceral hyperalagesia and was perscribed gabepentin which did work but side effects not good so am on pregablin whihc works very well for me!

    • Hi Charlotte
      Thanks for your comment. Drugs need to be used wisely as with any treatment and can play an important role. The prescriber must have experience and knowledge in pharmacology for children as they are not just mini-adults. In fact, many children do not use medication at all.
      There should be a plan for the medication and seeking to reduce the dose at some point.
      It appears that you both have a persisting pain issue, is that right?

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