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7 Articles in Volume 5, Issue #5
Effective Non-Drug Treatment of Depression
First Line Treatment of Musculoskeletal and Neuropathic Pain
Pain Drug Use Policy
Targeted Peripheral Analgesics in Chronic Pain Syndromes
Therapeutic Drug Monitoring
Tiredness and Chronic Pain Management
TMD/Facial Pain and Forward Head Posture

Targeted Peripheral Analgesics in Chronic Pain Syndromes

New compounding formulations and certain "off-label" uses of available analgesics—in topical and transdermal distribution—offer increased potency with fewer side effects to other body systems.

As the study of nociception and pain mechanisms progresses, we are gaining a better understanding of processes that promote, or sensitize the nervous system in a way that actually amplifies the experience of pain for the injured individual. Peripheral sensitization processes increase transduction and transmission of stimuli coded as painful, as well as promote spontaneous signaling miscoded as aberrant stimuli. Such dramatic peripheral activity subsequently leads to sensitization of central pathways which further amplify signaling and further exaggerates the pain experience. Over time, the site of pathology shifts from the direct processes of injury, to the sensitized nervous system to produce a neuropathic pain syndrome.1

Improved understanding of sensitization mechanisms has promoted a growing interest in addressing the peripheral processes directly as a way to reduce nociceptive signaling into the central nervous system (CNS).2,3 Impeding such input would thereby limit central sensitization processes as well.3-5 The most efficient treatment paradigms for any disease process focus treatment to the site of pathology.5,6 Targeted drug delivery methods reduce potential for side-effects, while maximizing drug exposure to the system to be treated.5-7 Due to these considerations, there is a growing interest in ‘targeted peripheral analgesics’ for further investigation and clinical use. Unfortunately, due to the use of medications for “off-label” purposes, and the lack of financial interest for sponsoring studies of “off-patent” drugs, the development of such specific analgesics remain impeded.

Compounding pharmacists have long been associated with reformulating—and often combining—various drugs with alternate delivery forms to reduce side-effects and improve compliance.6-8 At times, compounding a drug may exploit specific drug mechanisms to focus on an explicit pathologic process. Reformulating established drugs, altering the mode of delivery, and combining with other drugs for “off-label” uses is gaining acceptance and utilization, as evidenced by the growth of peer-reviewed literature.5-11

The purpose of this article is to focus on some of the currently used topical applications for pain management, as well as a few potentially evolving approaches.

Topical and Transdermal Delivery

The standard treatment of multiple chronic pain syndromes includes the use of multiple medications that may have limited affect yet multiple side effects. In order to provide care for these patients, doctors are often forced to “think outside of the box,” and rely on medications in an “off label” approach. As a result of such exploration, new uses and delivery methods have been developed for multiple medications. One such new approach is through the utilization of topical and transdermal medications that may potentially have greater effectiveness, with fewer side effects.5-9

The skin can be a very effective portal for drug delivery both locally, as well as systemically. The molecular characteristics of the drug and the solvent can favor either local (topical) or more systemic (transdermal) distribution. Topical formulations typically focus the medication to the localized region of the skin where it is applied. Advantages of this approach include drug delivery in a focused manner and potentially hundreds to thousand times greater concentrations than through oral or parenteral routes. Additionally, systemic side effects would be limited as well.5-7,11

Transdermal drug delivery, like parenteral routes, allows systemic distribution of multiple medications in a way that may potentially reduce GI side effects, as well as potentially allow higher systemic concentrations by bypassing liver first-pass metabolism. Other systemic side-effects, including CNS and cardiovascular responses, would remain of similar concern to oral routes.5,6,9

For the purposes of pain management, topical drug delivery can focus on the specific peripheral mechanisms, including transduction and transmission of nociceptive signaling, to hopefully limit both peripheral and central sensitization processes.1,5,10,12-14

Peripheral Nerve/Tissue Injury

Much of the initial stages of nerve sensitization involve direct peripheral nerve or adjacent tissue injury. Following a local injury, multiple local changes occur that sensitize the local sensory nerve fibers. Multiple substances are released into the milieu, such as acids, substance P, histamine to form a “sensitizing soup” that enhances neural discharges back to the central nervous system, but also enhances firing in adjacent neurons. Antegrade release of neurotransmitters adds further sensitizing substances to the mix. See Figure 1 for an illustration of these processes leading to peripheral sensitization. The net end result is decreasing activation thresholds in nociceptors, spontaneous discharges of nociceptors and axons, and multiple other processes termed peripheral sensitization. Subsequently this sensitization leads to increased quantity of up-regulated sodium and calcium channels in the regional sensory nerves, coupled with enhanced nociceptors sensitivity , increased frequency of spontaneous discharges within the regional neurons, and multiple other progressive processes (beyond the scope of this article) that increase pain signaling centrally.1 Topically applied local anesthetic drugs are the most commonly used agents to address this problem.5-7,9 The targeted administration of these agents may address the local chemical changes and more effectively inhibit the sensitizing processes. Topical agents that focus on the local milieu and processes may also produce fewer side-effects along with greatly enhanced efficacy.

Figure 1. Illustration of the transdermal application of topical agents to focus on the local milieu and peripheral sensitization processes.

Multiple over-the-counter (OTC) agents containing various local anesthetics have been widely used for years ( Solarcaine®). Clinically, topical Lidocaine, Bupivaciane and Tetraciane preparations are used in multiple forms, including lotions, creams, gels, sprays, and more recently patches.15,16 Direct application to wounds prior to bandage changes and debridements greatly improves patient comfort. A 5% lidocaine patch (Lidoderm®) has been shown to be effective for several pain syndromes including local/regional pain complaints, such as post-herpetic neuralgia; as well as more generalized pain complaints, such as low back pain.9,15,16 Additionally, certain antidepressants, such as amitriptyline and doxepin, can also block the sodium and calcium channels and act very similar to local anesthetics.6-8,10,14,17

In addition to the local anesthetic effects, there is good evidence that amitriptyline and similar antidepressants may block pain thru several different mechanisms. Norepinephrine and 5-HT reuptake inhibition; blocking of NMDA, nicotinic, histamine and 5-HT receptors; and activation of adenosine-1 receptors thru enhanced adenosine release are all potentially analgesic actions purported to this class of antidepressant.6,14,17

“Topical agents that focus on the local milieu and processes may also produce fewer side-effects along with greatly enhanced efficacy.”

Sensitization Leading to Chronic Neuropathic Pain

In addition to the upregulation of the various cationic and anionic channels, sensitization processes also involve production and transport of other receptor complexes both centrally and near the injury site that impact neural activity. NMDA, opioid, catecholamine, acetylcholine receptors are but a few of the multiple receptor mutations described as contributors to both peripheral and central sensitization processes.1,4,6,18

There are various syndromes that include the involvement of the sympathetic nervous system to either cause or promote chronic neuropathic pain.6,19,20 There appears to be an upregulation and an increased number of alpha-2 receptors which both register and also promote the release of sympathetic neurotransmitters epinephrine and norepinephrine.19 Alpha-2 receptors have been found to spread to coupling sites between the sensory and sympathetic nerves:

  1. within the neuroma at the injury site
  2. peripheral sympathetic fibers and an uninjured sensory nerve
  3. sympathetic fibers that sprout into the dorsal root ganglion.19,21

Sympathetic stimulation or norepinephrine can cause excitation of the nociceptive fibers, and incite pain by way of the alpha-2 receptors.19,21 The transdermal antihypertensive agent clonidine has been shown to be analgesic for localized sympathetically-mediated pain when the patch is placed proximate to the painful region.6,21,22 Clonidine’s action on the alpha-2 receptor is not locally restricted, but also spreads, through systemic distribution, to act at the dorsal root ganglion and other coupling sites between sympathetic and sensory fibers. Unfortunately, clonidine also interacts at other systemic and central alpha-2 receptor sites to produce undesirable symptoms including decreased blood pressure and sedation. There is a growing body of evidence that suggests tizanidine may offer some of the same benefits.8

The NMDA receptor has long been associated with central sensitization changes that lead to chronic neuropathic pain.1,2,6,18,20,23-25 Until recently, peripheral actions were not felt to be an active contributor to sensitization processes. NMDA receptors have been identified in peripheral C fibers in many regions, including various dermal regions.2,6,13,14 When activated by glutamate, which is common in inflammation and tissue injury, the NMDA receptors allow a cascade of events that include increased influx of calcium and sodium that lead to production of other sensitizing substances such as nitric oxide and various prostaglandins.1 Topical or regional application of such NMDA antagonists such as ketamine, memantine, or orphenadrine has been shown to considerably decrease regional pain.10,13,26-28 As a general dissociative anesthetic agent, ketamine has multiple side effects including hallucinations and increases in salivation. Topically-placed ketamine has minimal such side effects and is used frequently in compounded analgesics for various neuropathic pain syndromes, such as post herpetic neuralgia.5,6,8,9,14,26-28

Other drug classes appear to exhibit NMDA antagonism as well, including the opioids methadone,24,25 and levorphenol,23,29 the antiepileptic carbamazapine, and the antidepressant amitriptyline.6

There is also growing interest in controlling the local concentration of glutamate, the neurotransmitter associated with NMDA receptor activation. Glutamate is highly dependent on vesicle release from adjacent nerves through antegrade neurotransmission. Glutamate-containing vesicles dock with the neural membrane, fuse with the neurolemma (thin membranous sheath), and then are expelled outward through exocytosis. The docking of the neurotransmitter-containing vesicle is a very complex and pivotal mechanism that—if disrupted—can inhibit neurotransmitter release. Botulinum neurotoxins (Botox®) have been shown to inhibit various nociceptive processes by preventing the docking, subsequent exocytosis of acetylcholine, as well as other vesicle-dependent neurotransmitters.4 There is a suggestion, therefore, that the alpha-2-delta sub-unit of the N-type Ca2+ protein of the calcium channels play a role in such docking mechanisms30,31 and may be one of the sites of action for gabapentin and pregabalin.31 The synaptic vesicle protein SV2A is a binding site for the antiepileptic drug levetiracetam, and may potentially act within the docking mechanisms as well, by inhibiting the synaptic protein synaptotagmin1.32,33

Immune System Contribution

The immune system contributes to pain modulation at multiple sites from transduction through central processing in the brain stem. Shortly after a regional injury, TNF alpha interleukin 6 and interleukin 1 beta are released in the area, followed shortly by elevated levels in the dorsal horn. These sensitizing substances may increase signaling by essentially inserting into the neurolemma of the peripheral neuron to serve as a mutant ion channel, thereby increasing sensitivity as well as to potentially support spontaneous discharges.34,35 Thalidomide is a systemic drug that is well known for TNF alpha inhibition.34 Unfortunately, generalized use is quite complex due to its past history of birth defects, and the subsequent regulation required in order to prescribe this medication. Pentoxifylline is used to promote peripheral blood flow through its actions at the capillary level by inhibiting TNF-alpha, and has been shown to be analgesic as a topical agent in several studies.7,36

COX-2 Inhibition at Site of Injury

After any form of injury, a cascade of events occur within the local milieu surrounding the injury. Arachadonic acid from injured tissue cell wall structures is converted to a variety of prostaglandins by cyclooxygenase enzymes. Prostaglandins then promote the problematic inflammation and pain.1 Blocking the cyclooxygenase enzymes through any number of NSAIDs and COX-2 inhibitors reduce the prostaglandin production and thereby addresses pain and inflammation. Systemic distribution of prostaglandin inhibitors impact multiple other important prostaglandin-dependent functions of the body. As an example: renal, cardiovascular, and GI functions all maintain integrity through various prostaglandins and the cyclooxygenase enzymes that control the balance — specifically COX-1 vs. COX-2. Strongly inhibiting one of the COX enzymes may allow greater influence of the other enzyme. There is now a better understanding of the importance of this balance recently through the withdrawal of two COX-2 agents from the market, after a late observed trend toward adverse events was noted.

Interestingly, it appears that the COX-2 enzyme is a major contributor to both peripheral and central pain sensitization pathways.1 There is a growing body of evidence that suggests focused, locally applied COX-2 inhibitors near the site of injury, more directly impact peripheral sensitization along with secondary inhibition of central sensitization.6,9 Starting at the beginning of the cascade may be considerably more effective and safer than systemic drug distribution.

Topical anti-inflammatory delivery offers a potentially more favorable balance of the risk and benefits by completely bypassing such problematic areas as the GI and the cardiovascular systems.6,9,37 Topical NSAID’s exist in gel, spray and patch forms.6,7,9,37-39 By focusing on the site of the pathology, a topical NSAID would have its highest concentration at the source, including the dermis. The bioavailability in plasma concentrations of topical drug administration would allow only five to fifteen percent of that compared to systemic delivery.6,7,9,38,39 Adverse reactions occur in only 10-15% of the patients, are generally local issues, and with far fewer GI reactions.6,37,38 Effectiveness has been estimated up to 92% for certain peripheral pain problems.

Capsaicin and Transient Receptor Potential Channels

Transient Receptor Potential channels (TRP) are implicated as nociceptors for several painful stimuli. These channels allow increased electrolyte conductance as a result of several stimuli, such as changes in temperature, osmolality, peptides, and hydrogen ion content surrounding the neuron. There is an expanding number of identified TRP types, with the TRPV (vanilloid) as the most studied. The TRPV1 is a non-selective cation channel that is specifically activated by heat greater than 43 degrees; or capsaicin, the active agent in certain pepper plants.6,40,41 When the channels are activated, there is an increasing release of substance P (sP) and calcitonin gene-related peptide (CGRP) from peripheral and central terminals that promotes pain sensation.42 If there is repetitive TRPV channel activation, there is a desensitization process and a diminished sP and CGRP release over time.42,43 Low doses of 0.025 to 0.075% have been shown effective in several pain syndromes, but require repetitive use for several days to weeks before the response is noted.5,6,9

The painful burning sensation associated with the past use of capsaicin had previously limited compliance. More recently, however, it has been demonstrated that local anesthetic pretreatment allows the patient to tolerate potentially very high doses of capsaicin with limited discomfort.44-46 Concentrations of capsaicin reaching ten percent may be given in a short period of time to produce long lasting changes in the pain pathway.44 It now appears evident that it is not simply the depletion of sP and CGRP that is reducing the pain, but there is actually a neurolysis of fine epidermal nerve fibers. The neurotoxicity is partially osmotic and partially from excessive calcium which activates cellular proteases.43 Epidermal biopsies have clearly shown C fiber network neurolysis that can persist for five weeks or longer after a capsaicin treatment.47 Therefore, after such a neurolysis, several weeks of nerve re-growth must occur before pain may return.47

The TRPM-8 (melastatin) channel is activated by noxious cold sensations, near 20 degrees C and menthol. Interestingly, menthol activates the TRPM- 8 channels, to inhibit Ca2+ influx to produce a cooling sensation and block various pain types. When applied shortly before capsaicin, menthol appears to reduce the burning discomfort produced by activation of the TRPV channels.48 Menthol has also been proposed to act as a kappa opioid agonist as well.49

Topical Opioid Preparations

Classic opioid activity studies have focused on central sites, such as the dorsal horn (ex. substantia gelatinosa) and various brain regions (ex. periaquiductal gray). Peripheral opioid receptor existence has been somewhat controversial in the past. Evidence now supports that peripheral opioid receptors are produced in the dorsal root ganglion then transported both centrally and peripherally—especially after injury or inflammation.50,51 Various opioids, administered as either topical and regional preparations, have been shown to reduce pain responses.6,9,11,18,52-54 Local anesthetics appear to be synergistic with topical opioids as well. When applied to open ulcers, or other wounds, topical morphine has been shown to enhance healing.55 Like systemic opioids, tolerance to topical opioids has been reported. Such tolerance apparently is inhibited by coadministration of an NMDA antagonist, such as ketamine.56

Not all opioid preparations are purely topical or local in action. Fentanyl favors a transdermal to systemic distribution pattern. Central side-effects of opioids including sedation, euphoria, and dependence can still result if the topical dose is significant, or if vascular uptake is considerable. The anti-diarrheal agent loperamide (Lomotil) is actually a unique mu opioid agonist that lacks CNS side-effects because it does not cross the blood-brain barrier.52,53 Several studies have shown significant analgesic responses from topical loperamide.34,53,57-59

Cannabinoids as Topical Analgesics

Cannabinoids are highly controversial agents occasionally proposed as treatment of chronic pain. High abuse potential, necessary regulatory oversight, as well as social pressures, and inconsistent data regarding analgesia have all lead to heated debate on “medical marijuana.” Recent well-controlled studies have disproven analgesic benefit from systemic (smoked or orally administered) medical marijuana.60 Interestingly, investigation of specific peripheral cannabinoid receptors suggests analgesic effects from other drugs similar in structure to tetrahydrocannabinol (THC), the main agent in marijuana.

Two cannabinoid receptors, CB1 and CB2, are a focus of topical drug studies due to their reported analgesic effects. The CB1 receptors are found in the peripheral C-fibers and are associated with reduced calcitonin gene related peptide (CGRP) and decreased pain behavior response levels in the rat.61 CB2 receptors are found in various white blood cells and serve to modulate the release of regional endorphins.62 Currently, this author is unaware of published data on clinical use of topical cannabinoids, but would anticipate eventual studies.

“Compounding pharmacy experience in the literature provides new drug delivery options and expands the utility and effectiveness of existing drugs.”

Other Topical and Peripherally-Acting Analgesics

In addition to the previously reviewed agents, multiple other drugs have been proposed as potentially effective topical analgesics, including those that target bradykinin, nerve growth factor, ATP, various biogenic amines, GABA, and several prostanoids.6 Compounding literature also reports use of other agents with purported therapeutic actions, such as guaifenesin which is used as a type of muscle relaxant, or nifedipine used as an L-type calcium channel blocker.8 An exhaustive review of all current, off-label, and evolving topical approaches to chronic pain is beyond the scope of this rather brief review. A very thorough and informative review that explains the physiology and pharmacology of multiple agents, and mechanistic targets would include Dr. Sawynok’s paper “Topical and Peripherally Acting Analgesics.”6 Compounding journal articles often report formulations used for various drugs, as well as the supporting pharmacology.7,8 A brief list of topical compounded agents is listed in Table 1.

TOPICAL AGENTS FOR CHRONIC PAIN
Local Anesthetics
Lidocaine 2-10%
Tetracaine 2-10%
Bupivacaine 0.5% to 0.75%
Antidepressants (others)
Amitriptyline up to 10%
Doxepin up to 15%
NMDA antagonists
Ketamine 5-10%
Amantadine 5-10%
Dextromethorphan 5-10%
Orphenadrine 5-10%
a-2 Agonist
Clonidine 0.1%-0.2% transdermal as well Tizanidine*
Opioids (several others)
Morphine wide dose ranges
Methadone wide dose ranges
Loperamide: up to 10%
TNF-a antagonist
Pentoxifylline up to 10%
Glutamate antagonist
Gabapentin* 6-10%
L-Type Ca2+ Channel Blocker
Nifedipine 2-16%, depending on area size
Skeletal Muscle Relaxer*
Guaifenesin* up to 10%
Cyclobenzaprine 2-3%
Baclofen 2-5%
TRPV1 (vanilloid-1)
Capsaicin 0.05%-0.075% OTC and prescribed high-dose 7-10%; with local or regional anesthesia
TRPM8 (melastatin-8)
Menthol 5-10%, depending on size of treated region
NSAIDs
Diclofenac topical, 3% gel, Solaraze®
Ketoprofen 100mg patch, pending, 10-20%
Ibuprofen up to 5%
Piroxicam 2%
Indomethacin 10%
Aspirin in ether 5%
The above is a partial list of reported “off-label,” along with a limited number of drugs on-indication, reported to have been used for the treatment of chronic pain.8,63-66 Multiple other preparations have been described in other non-reviewed literature sources. Various solvents and absorption modifiers are often included in the formulation compound. The author and this journal assume no responsibility for the compounding and subsequent use of these specific agents. *Limited documentation and individual reports by compounding pharmacisits

Conclusion

When treating patients with chronic pain, doctors often face limitations in the drug armamentarium due to systemic side-effects and low potency of a specific drug in its primary mode of administration. Targeting the analgesic to the area of pathology, however, offers increased potency, with potentially fewer side-effects to other body systems that need not be involved in the drug exposure. The literature is rapidly expanding to identify new potential targets for such focused treatments of pain syndromes. Compounding pharmacy experience in the literature provides new drug delivery options and expands the utility and effectiveness of existing drugs.

Last updated on: December 28, 2011
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