The recent approval of a dermal capsaicin 8% patch with a long duration of action invites an examination of recent advances in the understanding of its therapeutic potential in neuropathic pain
Alain Borgeat MD
Head of Anaesthesiology Department,
CH-8008 Zurich, Switzerland
Neuropathic pain that can originate following injury to either the peripheral or central nervous system still remains a challenging condition to treat. Usual medications for neuropathic pain including antidepressants, antiepileptics, and opioids often fail to achieve satisfactory pain relief in a large number of patients.(1) Despite advances in the understanding of the pathophysiology and molecular biology of neuropathic pain, its clinical management is not only disappointing but also controversial. For example antidepressants and anticonvulsants are effective in less than half of patients.(2) Opioid use is often discouraged, because of concerns about ineffectiveness, the potential for the development of tolerance, the risk of addiction and limiting side-effects.(3)
In contrast to the strategy of attempting to interrupt nociceptive signalling pathways in the spinal cord or the brain, another approach is to reduce the persistent hyperactivity at the level of the injured peripheral nerve fibre. To support this hypothesis, it has been shown that continuous delivery of local anaesthetics such as lidocaine seems to provide significant pain reduction in patients with postherpetic neuralgia.(4)
Capsaicin is a selective agonist for the transient receptor potential vanilloid 1 receptor (TRPV1), which is preferentially expressed on small-diameter nociceptive neurons. TRPV1 is a molecular integrator of stimuli that are associated with tissue injury, such as heat, acidosis and inflammation mediators.(5) Topical application of capsaicin in humans initially activates cutaneous small-diameter sensory fibres, resulting in a burning sensation, erythema and enhanced sensitivity to noxious and innocuous stimuli. However, repeated topical application of capsaicin led to desensitisation and degeneration of epidermal nerve fibres (ENFs), which are predominantly C-fibre nociceptors.(6) Desensitisation coupled with an associated decrease of ENF density is the most likely mechanism for the therapeutic use of capsaicin in peripheral neuropathic pain syndromes.(7) This effect is reversible, and regeneration of ENFs coincides with return of the ability to detect painful sensations. It is expected that, following capsaicin exposure, sensation mediated by nonTVRP1-expressing cutaneous nerve endings remain unaltered.
Capsaicin has been licensed previously for postherpetic neuropathic and HIV pain, but the case study emphasises its efficacy in other clinical presentations of neuropathic pain, which still need to be investigated and validated.
Capsaicin dermal patch is an adhesive patch containing a high concentration (8% w/w) of synthetic capsaicin. Its indications and pharmacological properties are summarised in Table 1.
Studies have shown the efficacy of capsaicin in different conditions. Backonja et al(8) included 402 patients suffering from postherpetic neuralgia. They were assigned to one application of either 8% or 0.04% (control patch) capsaicin patch. In the 8% group, the mean pain was significantly reduced (–29.6% versus –19.9%) during weeks two to twelve after drug application. Transient blood pressure changes associated with changes in pain level were recorded on the day of treatment, and short-lasting erythema and pain at the site of application were common, self-limited and generally mild to moderate in 8% group. It was concluded that application of capsaicin 8% provided rapid and sustained pain relief without serious side effects in patients with herpetic neuralgia. The efficacy of capsaicin 5% in patients with HIV painful neuropathy was determined by Simpson and colleagues.(9) In a prospective double-blind, randomised, multicentre study, they assigned 307 patients to either capsaicin 8% or to a control patch (capsaicin 0.04%). A single 8% application resulted in a significant mean pain reduction of 22% versus 10.7% in the control group.
Following a transient treatment-related pain increase, pain was reduced, significant improvement was apparent by week two and maintained throughout the controlled 12-week observational period. The authors concluded that a single application of capsaicin 8% was safer and provided at least 12 weeks of pain reduction in patients with HIV-associated distal sensory polyneuropathy. The safety issue of repeated capsaicin 8% application was investigated by Simpson et al.(10) In this open-label study, patients suffering from HIV sensory polyneuropathy received up to three applications at intervals of >12 weeks. All patients were followed up for 48 weeks. The most frequently reported treatment-emergent adverse events were transient, mild-to-moderate application size erythema, pain, oedema and papules. Small, transient pain-related increases in blood pressure during and immediately after capsaicin 8% application were observed. Importantly, there was no evidence of serious side effects such as dermal irritation, intolerability, or impaired neurological function secondary to repeated application. Therefore, the authors concluded that repeated application of capsaicin 5% administered over a one-year period is generally safe and well tolerated.
Some issues regarding capsaicinoids (such as capsaicin) still need to be addressed. Although this family of compounds has been investigated extensively, their clinical applications are still limited so far, owing to their low selectivity and toxic potential. It is well accepted that capsaicinoids are agonists of TRPV1. However, the precise mechanisms for the interaction between these drugs and TRPV1 are still not clearly defined. Progress made in this regard may help to look for the ‘best capsaicinoid’ structure in order to achieve the best therapeutic potential and the lowest toxic potential. In addition, the ‘precise’ indications for capsaicin need to be defined. Among the many manifestations of neuropathic pain, those that can be treated efficiently with this compound need to be refined. These issues should be the topic of future investigations.
A 46-year-old male, American Association of Anesthesiologists physical classification 2, had undergone a right nephrectomy through an antero-lateral approach 12 months previously. Surgery and anaesthesia were uneventful. His past medical history was unremarkable except for an isolated incident of opioid abuse ten years before. He successfully completed a rehabilitation programme without any subsequent episodes of relapse.
A few days after discharge, the patient started to feel numbness over and around the surgical incision on the right lower quadrant of the abdomen. During the following days the numbness evolved into a hypersensitivity to touch. He could barely wear clothing and could not tolerate any covers in that area. He also had excruciating stabbing pain, which worsened with exercise, coughing or hip flexion. His general practitioner prescribed paracetamol 4 x 1g/24hours and metamizole 4 x 1000mg/24hours. No non-steroidal anti-inflammatories were given because of the nephrectomy. No improvement occurred with this treatment and the patient was referred to a neurologist. His examination was positive for allodynia and hyperpathia and the diagnosis of postoperative neuropathic pain was made with the possible involvement of the right ilio-hypogastric nerve. A treatment with carbamazepine at 800mg/24 hours was initiated, which subsequently was increased to 1000mg/24 hours. No improvement was noticed and a trial with oxycodone 20mg/24 hours was started. This drug had to be stopped quickly because the patient became aggressive and confused. Pregabaline was initiated, but at a dose of 150mg/day the drug was discontinued because of intolerable symptoms of fatigue, dizziness and visual disturbance. At this point, the possibility of a surgical decompression of the ilio-hypogastric nerve was discussed, but refused by the patient. It was proposed to block this nerve and the patient was referred to our institution.
A percutaneous test infiltration with 5ml ropivacaine 0.5% and 80mg triamcinolone was performed. The pain was improved from Visual Analogue Scale (VAS) 90 to VAS 50. A transcutaneous phenol neurolysis with 4 ml phenol 7.5% was performed. The pain was initially improved; VAS was 30 for the first four weeks. However, the pain slowly returned and two months later the pain was back to VAS 90. Then, as a last therapeutic resort, application of a capsaicin 8% topical patch was intiated.
Prior to its application, we used a continuous infusion of remifentanil for pain control. After recording the vital signs, a venous access was placed. Target infusion of remifentanil was started to reach an effect site concentration of 0.8ng/ml. The patch was applied tightly for 60min and covered with a tegaderm and gauze bandage to improve skin contact. The patient had pain and redness for the first 48 hours, which were treated with cold patches and paracetamol. Forty-eight hours after the capsaicin application, the pain was reduced from VAS 90 to 20. One week later pain intensity was scored as 0. One year later, without the need of subsequent capsaicin application, the patient is pain free.
- Neuropathic pain still remains a challenging condition to treat.
- Capsaicin is effective at the level of the injured peripheral nerve.
- Studies have shown its efficacy in different conditions including postherpetic neuralgia and HIV painful neuropathy.
- First investigations did not show any evidence of serious side effects.
- Further studies are still needed to elucidate the exact interaction between capsainoids and TRPV1 and to define the best indications for this treatment.
- Harden N, Cohen M. Unmet needs in the management of neuropathic pain. J Pain Symptom Manage 2003;25:S12–7.
- Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999;83:389–403.
- Carver A, Foley K. Facts and an open mind should guide clinical practice. Curr Neurol Neurosci Rep 2001;1:97–8.
- Katz NP et al. Lidocaine patch 5% reduces pain intensity and interference with quality of life in patients with postherpetic neuralgia: an effectiveness trial. Pain Med 2002;3:324–32.
- Caterina MJ et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389:816–24.
- Bjerring P, Arendt-Nielsen L. Use of a new argon laser technique to evaluate changes in sensory and pain thresholds in human skin following topical capsaicin treatment. Skin Pharmacol 1989;2:162–7.
- Bley KR. Recent developments in transient receptor potential vanilloid receptor 1 agonist-based therapies. Expert Opin Investig Drugs 2004;13:1445–56.
- Backonja M et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol 2008;7:1106–12.
- Simpson DM, Brown S, Tobias J. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology 2008; 70:2305–13.
- Simpson DM et al. Long-term safety of NGX-4010, a high-concentration capsaicin patch, in patients with peripheral neuropathic pain. J Pain Symptom Manage 2010;39:1053–64.