Capsaicin and Neuropathic Pain

By Robert Lutz, MD, MPH

Neuropathic pain describes a diverse group of chronic pain syndromes that affects up to 1.5% of the U.S. population.1 Patients experiencing neuropathic pain represent approximately 50% of visits to pain centers, and their clinical conditions present challenges to successful therapeutic management.2 Examples include: post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, HIV polyneuropathy, neuropathic low back pain, post-stroke pain, post-mastectomy pain, phantom limb pain, and complex regional pain syndrome (CRPS), types I and II. The pain is described variably as burning, lancinating, electric, deep, or shooting. The cardinal signs are allodynia (the perception of a non-noxious stimulus as painful) and hyperalgesia (an excessive response to painful stimuli).

People with chronic pain may be unable to identify an antecedent event, and reasons for its persistence may not be readily apparent to either the individual or clinicians. The condition may affect multiple aspects of an individual’s life including physical functioning, psychological health, social interactions, and societal functioning. Whereas a number of pharmacological (e.g., tricyclic antidepressants, anticonvulsants, and antiarrhythmics) and non-pharmacological (e.g., nerve stimulation and psychological treatments) interventions currently are available with variable success, capsaicin represents an interesting natural alternative.

Botanical Information and Traditional Use

Chili peppers (Capsicum frutescens) are members of the Solanaceae, or nightshade, family. They are native to South America where they have been cultivated for thousands of years as a perennial. Upon introduction to other parts of the world in the 16th century, they became inappropriately linked to black pepper due their similarity in pungency and were called "red peppers." The substance that gives chili peppers their heat, capsaicin, is believed to have evolved as a protective mechanism against foraging mammals. In contrast, birds do not have an adverse response to capsaicin and probably contributed to their wide distribution throughout northern South America and Central America via seed dispersal.

It is estimated that chilies are regularly consumed by more than a quarter of the world’s population. Their medicinal and non-culinary uses have included: the relief of toothaches by Native Americans; as an aphrodisiac, a digestive aid, a cough expectorant, and a stimulant; and for rheumatism, dyspepsia, and postoperative analgesia.3 Legend has it that the Incas used burned dried chilies to ward off the invading Spanish.4 This last use is probably familiar to readers as it is currently used in defensive sprays to ward off criminals as well as animals.

Chemistry and Mechanism of Action

Capsaicin is lipophilic, hydrophobic, and very soluble in alcohol. It was first isolated in the mid-1800s by Thresh and its chemical structure (N-Vanillyl-8-methyl-6-(E)-noneamide) was determined in the early 1900s by Nelson.5 Its unique ability to "desensitize" afferent pain neurons (nociceptors) with repetitive applications was determined by Jansco,6 and it is this attribute that has made it of interest to researchers.

The gene for the capsaicin receptor was identified only very recently.7 This nocireceptor, the vanilloid receptor (TRPV1), has been found on the afferent neuronal membranes of C-fibers (small-diameter, unmyelinated, slow-velocity conduction), a smaller population of Ad fibers (medium-diameter, partially myelinated, intermediate-velocity conduction), and is sensitive to all three pain modalities (mechanical, chemical, and thermal). It is believed that the primary function of this receptor is to provide integration of chemical and physical stimuli, especially thermal stimulation (> 43° C) and low pH. Capsaicin and acidification lower the threshold for receptor stimulation.8 These receptors are found in the skin, cornea, and mucus membranes of the mouth, as well as skeletal muscle and joints, and organs of the cardiovascular, respiratory, and genitourinary systems (of note, these visceral receptors function at both a reflex autonomic level as well as a conscious perceptual level).

Upon stimulation of the TRPV1, a cascade of neurogenic inflammation occurs that serves to enhance pain and possibly produce hyperalgesia in the affected tissues. This cascade is characterized by excitation, desensitization, and tachyphylaxis.

Excitation. Peripheral topical stimulation of the TRPV1 by capsaicin causes transmission of nerve impulses centrally, where they synapse in the dorsal horn of the spinal cord and produce the pain response, mediated through glutamate. Pro-inflammatory peptides, such as Substance P (SP) and calcitonin gene-related peptide (CGRP), are released peripherally in the efferent element of these neurons, producing the sensation of pain or itch, as well as sometimes producing a flare response seen at a distance from the injury site (SP produces plasma extravasation and edema formation while CGRP triggers vasodilation). Following neuronal activation, there is a period of enhanced sensitivity to noxious stimuli (hyperalgesia and allodynia) mediated through nitrous oxide, the release of glutamate, and the activation of N-methyl-D-aspartate (NMDA) receptors. This initial increased sensitivity to painful stimuli is extinguished with repeated exposure to capsaicin as neurotransmitters are depleted and synthesis is blocked, providing a prolonged analgesic effect (desensitization).

Desensitization and Tachyphylaxis. Following excitation, a refractory period of pain sensitivity of variable duration occurs. Sensitized neurons neither respond to repeated capsaicin challenge nor to other stimuli, such as heat or chemicals. Histological changes have been identified in animal models9 and in humans.10 These changes are characterized by a down-regula- tion of TRPV1s in the epidermis and subepidermis. Additionally, capsaicin down-regulates the release of SP, thereby depleting stores and providing the mechanism for clinical application of cutaneous capsaicin. Repeated applications of gradually increasing doses of capsaicin can prolong this period of desensitization and tachyphylaxis.

Pathophysiology and Clinical Rationale

Capsaicin currently is used topically (for neuropathic pain and other pain disorders, dermatological disorders, and muscle ache), intranasally (for treatment of cluster headaches, vasomotor rhinitis, and perennial allergic rhinitis), and for intravesical infusion (bladder hypersensitivity and spinal detrusor hyperreflexia). The topical application of capsaicin for neuropathic pain will be the focus of the following material.

Neuropathic pain results from a lesion within the peripheral or central nervous systems, or a dysfunction in one or both of these systems. The pathophysiological explanation is complex and continues to be investigated. There is growing appreciation of a role for elements of the nervous system not previously believed to be involved with pain transmission. Additionally, the autonomic nervous system often is affected, as seen in individuals with CRPS. For example, recruitment of afferent and efferent nerves after insult may explain referred pain patterns, phantom pain, or allodynia. "Central sensitization" (the process by which the nervous system responds to pain more easily following injury2) leads to a lowering of the pain threshold, facilitating pain transmission and leading to an increased sensitivity to nociception and actual neurophysiological changes within the central nervous system, especially the spinal cord. Up-regulation of glutamate and increased activation of the NMDA receptor are responsible for this phenomenon.

In normal pain transmission, impulses travel primarily along C-fibers and to a lesser extent along Ad fibers. These afferent neurons synapse with second-order neurons in the dorsal horn of the spinal cord. Release of glutamate elicits the acute pain response. Glutamate is an excitatory neurotransmitter and may be metabolized to gamma-aminobutyric acid, an inhibitory neurotransmitter. In normal situations, these neurotransmitters exist in balance. This balance is offset in neuropathic pain, however, leading to increased levels of glutamate released into the synaptic cleft with the second-order neuron in the dorsal horn. NMDA receptors, stimulated by glutamate release, in combination with NK1 receptors stimulated by SP, provide an enhanced signal for pain recognition. With neuropathic pain there is an up-regulation of the NMDA receptor as well as enhanced release of SP and glutamate.

For the clinical treatment of neuropathic pain, capsaicin has been delivered primarily as a topically applied cream in concentrations of 0.025% or 0.075%. It is typically applied sparingly 3-4 times per day to the affected area for a period of 4-6 weeks. As described previously, the mechanism by which capsaicin produces its effects elicits initial discomfort with topical application, followed by an eventual decline with repeated use. For this reason, capsaicin has been called a "counter-irritant." Studies have looked at its use in post-mastectomy pain;11 stump pain;12 CRPS;13 periocular pain;14 trigeminal neuralgia;15 post-herpetic neuralgia; and diabetic neuropathy. Its efficacy has been challenging to assess in research due the high dropout rates and to an inability to adequately blind participants, in spite of attempts to lessen the discomfort with the co-administration of local anesthetics. Additionally, with the exception of the latter two conditions mentioned above, studies most often have been case reports or only recruited small numbers of participants. The low concentration used in these topical creams also is unlikely to adequately cause desensitization of afferent cutaneous nerve endings. Therefore as a solo agent, capsaicin cream probably has a limited role in the management of neuropathic pain.16

However, clinical trials using topical capsaicin cream as an adjuvant therapy in post-herpetic neuralgia have been promising. Peikert et al reported a ~40% reduction in pain intensity in patients using capsaicin cream (0.025%) four times a day for eight weeks in a noncomparative study.17 Other studies have reported similar findings.18,19 Although methodological considerations prevent drawing firm conclusions, patients generally reported reduction in pain intensity. It has been suggested that this improvement may be sustained with longer usage.20 Randomized clinical trials comparing topical capsaicin with other pharmacological agents are not available.

Topical capsaicin likewise has demonstrated potential efficacy in clinical trials looking at diabetic neuropathy. Data from the Capsaicin Study Group found capsaicin cream (0.075%) applied to the affected area four times per day for a period of eight weeks superior to placebo in pain improvement (69.5% vs. 53.4%, P = 0.012), pain intensity (38.1% vs. 27.4%, P = 0.037), and pain relief (58.4% vs. 45.3%, P = 0.004).21 Improvement in activities of daily living (ADLs) also was noted. A significant placebo response was identified.

A meta-analysis of four clinical trials of subjects with neuropathic pain comparing topical capsaicin cream (0.075%) to placebo demonstrated a significant benefit for capsaicin cream (odds ratio = 2.74, 95% confidence interval 1.73-4.32).22 A single randomized trial comparing capsaicin cream 0.075% (applied four times daily) with oral amytriptyline (25 mg/d-125 mg/d) for eight weeks found equal improvement in pain severity, pain relief, and ADLs as compared to baseline.23

Recently, a novel approach using significantly higher doses of topical capsaicin (7.5%-10%) applied under regional anesthesia has provided promising results. Individuals with CRPS, diabetic neuropathy, HIV-associated neuropathy, and post-herpetic neuralgia have been treated and experienced pain relief for up to several months.24,25

Adverse Effects

Other than the aforementioned burning sensation, topical capsaicin is considered a very safe pharmaceutical. Reports of respiratory problems (coughing and sneezing) have been noted.21

Whereas concern has been raised that capsaicin may be cancer-causing, as demonstrated in vitro26 and in animal studies,27 it is recognized that liver metabolites of capsaicin are responsible for its mutagenicity. Therefore, topically applied capsaicin is probably safe for use.4 A case control study has suggested that excessive consumption of chilies may be associated with an increased risk of gastric cancer.28 Methodological considerations limit the data from this study, however, and conflicting studies have been produced.29 Therefore, excessive consumption of chilies should probably be discouraged until further data are available.

Conclusion

Chili peppers have a long history of traditional use in medicine. Recent research has elucidated the mechanism of action of capsaicin, the active ingredient in chilies. Although its use in a number of medical conditions, and especially in neuropathic pain, has been limited by its pungency, study of capsaicin has greatly aided the understanding of pain. Continued research may demonstrate increased use for this natural medicine.

Recommendation

Topical capsaicin has a limited role as a primary analgesic for neuropathic pain. It does, however, provide a natural adjunctive therapy for this condition. Topical application of capsaicin, in doses of 0.025%-0.075%, requires frequent administration (3-4 times daily) for a minimum of 4-6 weeks before its therapeutic effects can be assessed adequately. Buffered formulations (e.g., menthol) may lessen the discomfort that occurs during the first few weeks of use. Patients should be advised to use gloves when applying; to avoid application near open wounds; and to avoid rubbing other areas of the body, especially the eyes and mucus membranes.

Dr. Lutz is Assistant Research Professor, College of Medicine and the Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson.

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