Publications
APS Bulletin • Volume 9, Number 2, March/April 1999
Research Update
Richard H. Gracely, PhD, Department Editor
Adjuvant Agents for Managing Chronic Pain
Amy L. Whitaker, PharmD; Daniel T. Kennedy, PharmD BCPS; Ralph E. Small, PharmD FCCP FASHP FAPhA
Chronic pain is difficult to define briefly. It is understood to be a persistent pain that frequently is not amenable to routine pain control methods (Merskey & Nogduk, 1994). For some patients, chronic pain may develop when pain persists beyond the expected time of healing. Other patients may never experience the healing process. Because there are many differences in what is regarded as chronic pain, management strategies remain flexible and related to specific cases.
Pathophysiologic classification of pain may assist in selecting appropriate therapies and determining a prognosis for patients (Foley, 1994). There are four major categories into which chronic pain can be classified: nociceptive, neuropathic, mixed, or unknown origin. Nociceptive pain can be either visceral or somatic; it is derived from stimulation of pain receptors (Meyer, Campbell, & Raja, 1994). Development of nociceptive pain may be due to the inflammation, mechanical deformation, ongoing injury, or destruction of tissue. Neuropathic pain involves a pathophysiological process in either the peripheral or central nervous system (CNS) or both (Bennett, 1994). Examples of neuropathic pain include trigeminal neuralgia, postherpetic neuralgia, poststroke central or thalamic pain, and phantom limb pain. Chronic pain can have mixed or unknown mechanisms or it can be psychological in nature (Craig, 1994). These types of pain are unpredictable and difficult to treat.
Because many different neurotransmitters (e.g., substance P, serotonin, prostaglandins, bradykinin, leukotrienes, histamine) and receptors (e.g., opioid, serotonin, acetylcholine, dopamine, norepinephrine) are involved in pain, many potential targets for drug therapy exist. The selection of an appropriate analgesic medication can be difficult. The World Health Organization (WHO) has developed a three-step approach for selecting analgesics for the management of chronic pain (Montauk & Martin, 1997). (Not all physicians use the WHO three-step approach universally, and this approach may not represent a routine procedure to be employed for all chronic pain patients.) The first-line agents are acetaminophen and nonsteroidal antiinflammatory drugs. If pain relief does not occur with these agents, low-dose opioid combinations such as acetaminophen with codeine (Tylenol No. 3®), acetaminophen and hydrocodone (Lortab®, Vicodin®), and acetaminophen with oxycodone (Percocet®) can be used. If the pain is still not controlled, stronger opioids such as morphine, hydromorphone, and methadone can be used. For patients who still do not achieve adequate pain control, it may be necessary at this point to consider adjuvant analgesic therapy. Adjuvant agents are not typically thought of as having analgesic properties. However, they are helpful in maximizing pain control and lowering the required dosage of opioids, and they can be used in combination with the above-mentioned therapies.
The largest body of literature on adjuvant agents focuses on the use of antidepressants, specifically tricyclic antidepressants (TCAs), and their role in nociceptive and neuropathic pain (Onghena & Van Houdenhove, 1992). Newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have also been studied for their role in chronic pain management. The mechanism of action for TCAs is unknown; the analgesic effect may be due to an increase in norepinephrine levels in the CNS (Bushnell & Justins, 1993). It is hypothesized that SSRIs increase serotonin levels in the CNS and thus affect the pain modulating system in the brain (Rani, Naidu, Prasad, Rao, & Shobah, 1996) The analgesic effect often occurs with a lower dosage than is required for antidepressant activity. However, the dosage can be increased according to patient response. The onset of analgesic effect is often seen in a matter of days, rather than the 6-8 weeks required for relief of depression (Bushnell & Justins).
TCAs such as amitriptyline (Elavil®), desipramine (Norpramin®), doxepin (Sinequan®), imipramine (Tofranil®), and nortriptyline (Pamelor®) have been studied for their role in treating neuropathic pain. Low-dose amitriptyline has been demonstrated to be especially beneficial in postherpetic neuralgia and poststroke pain syndromes (McQuay, Carroll, & Glynn, 1992). Amitriptyline has also been shown to be beneficial in nociceptive pain, especially somatic pain (Gorelick et al., 1998). Several studies have examined the use of SSRIs in fibromyalgia and diabetic neuropathy. Fluoxetine (Prozac®) has been shown to be effective in reducing pain and improving global wellness scores in patients with fibromyalgia, especially when used in combination with amitriptyline (Goldenberg, Mayskiy, Mossey, Ruthazer, & Schmid, 1996). In evaluating the use of SSRIs in diabetic neuropathy, paroxetine (Paxil®) has been demonstrated to produce an improvement in patients' pain compared with a placebo. However, the effect was less than that of imipramine (Sindrup, Gram, Bronsen, Eshoj, & Morgensen, 1990). In patients suffering from neuropathic or nociceptive pain, traditional antidepressants such as TCAs have been well studied and proved to be effective. These agents should be used first and titrated slowly to effect.
Anticonvulsants have also found a role in chronic pain management. These agents have been shown to be beneficial in treating epiletiform-like bursts of spontaneous lightning or shooting pain that manifest from neural damage (McQuay, Carroll, Jadad, Wiffeh, & Moore, 1995). A number of studies have been completed using anticonvulsants in trigeminal neuralgia and diabetic neuropathy. Much of the literature has evaluated traditional neuroleptic drugs such as carbamazepine (Tegretol®) and phenytoin (Dilantin®), which have proved to be particularly beneficial in trigeminal neuralgia (McQuay et al., 1995). The mechanism of action for these agents is believed to be related to a blockade of sodium channels that inhibits transmission of excitatory impulses (Macdonald & Kelly, 1994). In one study conducted by Campbell, Graham, and Zilkha (1966), carbamazepine was shown to decrease pain severity 58% in patients suffering from trigeminal neuralgia. Other studies have shown a similar response (McQuay et al., 1995). Phenytoin has been evaluated in treating diabetic neuropathy with conflicting results. A 5-week evaluation of phenytoin at 300 mg per day showed a response and improvement in pain intensity. However, a 46-week evaluation of phenytoin at 300 mg per day showed no significant difference between phenytoin and a placebo in affecting pain intensity (Chadda & Mathur, 1978; Saudek, Werns, & Reidenberg, 1977). Although these agents have been shown to be effective, they are not without frequent adverse effects and limitations in efficacy.
A newer antiepileptic agent, gabapentin (Neurontin®), is being evaluated in the treatment of chronic pain. Case reports have been published on the role of gabapentin in several pain and movement disorders (Merren, 1998). It has been proposed that the mechanism of action for gabapentin is related to pre- or postsynaptic regulation of glutaminergic receptors or that gabapentin potentiates gamma-aminobutyric acid (GABA) adrenergic function without direct stimulation of GABA-benzodiazepine receptors (Singh et al., 1996; Swinyard, Sofia, & Kupferberg, 1986). Analysis demonstrated a response rate of 50% in patients with polyneuropathy and trigeminal neuralgia receiving gabapentin, whereas little to no response was seen in patients with multiple sclerosis, cerebellar tremor, or central pain (Merren). It is relatively simple to initiate gabapentin therapy, and it has fewer drug interactions and side effects than older anticonvulsants. However, more research is needed to define the role of gabapentin in chronic pain.
N-methyl-D-aspartate (NMDA) receptor antagonists have long been used to help manage neuropathic pain. The activity at this receptor is believed to be involved with the "wind-up firing" of dorsal horn neurons, which can result from repeated C-fiber stimulation (McQuay, et al., 1994). Dextromethorphan and ketamine are two currently available NMDA receptor antagonists. Ketamine has been used to treat conditions such as postherpetic neuralgia, chronic posttraumatic pain, and pain associated with lesions in the central nervous system (Nelson, Park, Robinovitz, Tsigos, & Max, 1997). However, side effects associated with its use have limited its clinical application (Nelson et al.). Dextromethorphan is a low-affinity NMDA receptor antagonist that is rapidly metabolized in the body to dextrorphan, an active metabolite that also has NMDA receptor activity (Nelson et al.). In trials conducted with dextromethorphan, results in response to treatment have been mixed (McQuay et al., 1994; Price, Mao, Frenk, & Mayer, 1994). In a study conducted by Nelson and colleagues, patients suffering from diabetic neuropathy and postherpetic neuralgia were given dextromethorphan (initial dose 120 mg per day, maximum dose 960 mg per day). When compared to placebo results, the pain assessment scores of patients with diabetic neuropathy were significantly improved, and the response in patients with postherpetic neuralgia was improved. A hypothesis as to the difference in response is that NMDA receptor antagonists are particularly beneficial in patients with ongoing peripheral neuron damage, as seen in diabetic neuropathy, but not in patients with fixed lesions, which are common in postherpetic neuralgia (Nelson et al.) Studies in progress are attempting to determine the dosage of dextromethorphan needed to maximize analgesic benefit.
Tramadol is indicated for patients with pain from osteoarthritis, neuropathic pain, low-back pain, or postsurgical joint replacement (Katz, 1996). It is a weak agonist for all opioid receptors, but it also inhibits norepinephrine reuptake and stimulates the release of serotonin (Montauk & Martin, 1997). This mechanism is significant, because tramadol appears to act at multiple places in the nociceptive pathway. Although its affinity for m receptors is 10 times less than that of codeine and 6,000 times less than that of morphine, it is still considered a strong analgesic, and it has a place in the second step of the World Health Organization pain management strategy (Aronson, 1997; Montauk & Martin). In clinical trials involving patients suffering from chronic pain, tramadol was found to be no more effective than acetaminophen and codeine combinations (Rauck, Rouff, & McMillen, 1994). Side effects associated with tramadol use are few, although seizures have been reported at recommended doses (Kahn, 1997).
Because tramadol's mechanism of action is similar to that of opioids, it is reasonable to consider that its use may produce some of the same tolerance, dependence, and abuse issues associated with opioid use. Tramadol is currently available in the United States on nonscheduled status, unlike opioids, which are scheduled into different controlled classes depending on composition. The FDA is currently reviewing tramadol for scheduled status. Recent evidence points to a minimal potential for abuse compared with that of other opioid analgesics (Aronson, 1997). Tramadol tolerance is mild, and symptoms of withdrawal, if present, are considerably less noticeable than the withdrawal symptoms experienced with opioids. Patients who had been addicted to pain medication were not able to distinguish tramadol from a placebo; however, they were able to correctly identify morphine when it was administered (Aronson). Evaluation by the German Substance Abuse Warning System indicates that tramadol is less likely to be abused than codeine. (Katz, 1996). However, there is concern that the data reporting abuse may reflect that tramadol use is relatively low in comparison with other agents that are more widely prescribed and abused throughout Europe (Katz). Reports filed with MedWatch and the Drug Abuse Warning Network in the United States indicate that dependence has occurred in patients using tramadol. These reports are under consideration by the FDA in its review of tramadol for scheduled status (FDA, 1998).
Capsaicin (Zostrix®), a pungent and irritating compound found in red peppers, has been used topically for centuries to relieve pain (Fusco & Giacovazzo, 1993). Because it appears to act on a defined set of sensory neurons involved in nociception, capsaicin's role in pain management merits examination. The primary effects of capsaicin are related to its activity in the peripheral portion of the sensory nervous system. It works to excite nociceptive C-afferent neurons, causing the release of substance P, which is essential for transmission of nociception to occur in the nervous system. Repeated application of capsaicin depletes substance P, leading to inhibition of pain sensation (Markovits & Gilhar, 1997). Capsaicin has been used to help manage pain in many different conditions, including diabetic neuropathy, postherpetic neuralgia, rheumatic diseases, postmastectomy pain, and cluster headaches. Clinical trials performed in patients with diabetic neuropathy demonstrated a 50% improvement in pain status with use of capsaicin for 22 weeks (Tandan, Lewis, Krusinsky, Badger, & Fries, 1992). Commonly reported side effects associated with the use of capsaicin include burning and stinging at the area of application. Evaluation of patients using capsaicin demonstrated a change in warmth and sensation thresholds upon initial application. However, after 8 weeks of repeated application, the same patients demonstrated no significant change in warmth or sensation perception (Tanden, Lewis, Badger, & Fries, 1992). It can be concluded that the local reaction following application of capsaicin may be most intense at the beginning of therapy and could subside with continued use.
In the past several years, there has been an explosion of nontraditional nonprescription preparations into the healthcare marketplace. In a survey conducted in 1997, 42% of Americans reported using alternative medications during the past year (Eisenberg et al., 1998). As alternative medicine grows in popularity, it is important to understand the claims these products make. Many are marketed as nutritional supplements and therefore are not regulated by the FDA. However, many implied benefits are reported on the labels.
One of the most publicized products on the alternative medicine market is glucosamine. It is used in the treatment of osteoarthritis where destruction of cartilage has taken place. Glucosamine has been hypothesized to impede the breakdown of cartilage and to help regenerate cartilage. Some antiinflammatory properties may be associated with glucosamine as well. One study showed that in comparison with placebo, patients responded positively to glucosamine at 500 mg three times daily and reported a significant improvement in pain, morning stiffness, mobility, and general activities (Pujalte, Llavore, & Ylescupidez, 1980). Another study showed a positive effect of intramuscular glucosamine compared to placebo treatment over a 6-week period (Reichell, Fonter, Rovati, & Setnikar, 1994). Although these studies evaluating glucocosamine suggest some benefit, they are not without serious flaws in design. The most commonly reported adverse effects were gastrointestinal upset and rash. It is important to remember that long-term studies examining glucosamine have not yet been conducted. Concern exists about the implications of altering cartilage breakdown and formation in the body and possible associated toxicities. Alternative therapy with preparations such as glucosamine should not take the place of proven methods of treating osteoarthritis. Glucosamine is an adjunct therapy for osteoarthritis worth considering when traditional therapy fails.
Chronic pain will remain an issue for many patients who have failed traditional analgesic therapy administered in accordance with treatment guidelines. Practitioners must not only recognize chronic pain but also aggressively treat the condition. Whenever possible, treatment should be proactive rather than reactive. Adjuvant agents are not considered first-line therapy in pain management. Instead, they optimize pain control and provide relief to patients who suffer from intractable pain. Management of chronic pain is a complex process requiring appropriate medication management as well as treatment of the whole person. A management strategy must be tailored to individual patient needs and situation, and must be constantly reviewed to ensure optimal patient outcome.
References
Aronson, M.D. (1997). Nonsteroidal anti-inflammatory drugs, traditional opioids and tramadol: Contrasting therapies for the treatment of chronic pain. Clinical Therapeutics, 19, 420-432.
Bennett, G.F. (1994). Neuropathic pain. In P.D. Wall & R. Melzack (Eds.), Textbook of pain (3rd ed., pp. 201-224). New York: Churchill Livingstone.
Bushnell, T.G., & Justins, D.M. (1993). Choosing the right analgesic: A guide to selection. Drugs, 46, 394-408.
Campbell, F.G., Graham, J.G., & Zilkha, K.J. (1966). Clinical trial of carbamazepine (Tegretol) in trigeminal neuralgia. Journal of Neurology, Neurosurgery, and Psychiatry, 29, 265-267.
Chadda, V.S., & Mathur, M.S. (1978). Double blind study of the effects of diphenylhydantoin sodium on diabetic neuropathy. Journal of the Association of Physicians of India, 26, 403-406.
Craig, K.D. (1994). Emotional aspects of pain. In P.D. Wall & R. Melzack (Eds.), Textbook of pain (3rd ed., pp. 261-274). New York: Churchill Livingstone.
Eisenberg, D.M., Davis, R.B., Ettner, S.L., Appel, S., Wilkey, S., Van Rompay, M., & Kessler, R.C. (1998). Trends in alternative medicine use in the United States. Journal of the American Medical Association, 280, 1569-1575.
Foley, K.M. (1994). Pain management in the elderly. In W.R. Hazzard, E.L. Bierman, J.P. Blass, W.H. Ettinger, & J.B. Halter (Eds.), Principles of geriatric medicine and gerontology (3rd ed., pp. 317-331). New York: McGraw Hill.
Food and Drug Administration (FDA). (May 4, 1998). The pink sheet. Washington, DC: Author.
Fusco, B.M., & Giacovazzo, M. (1993). Pepper and pain: The promise of capsaicin. Drugs, 56, 909-914.
Goldenberg, D., Mayskiy, M., Mossey, C., Ruthazer, R., & Schmid, C. (1996). A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis & Rheumatism, 39, 1852-1859.
Gorelick, A.B., Koshy, S.S., Hooper, F.G., Bennett, T.C., Chey, W.D., & Hasler, W.L. (1998). Differential effects of amitriptyline on perception of somatic and visceral stimulation in healthy humans. American Journal of Physiology, 275, G460-G466.
Kahn, L.H. (1997). Seizures reported with tramadol. Journal of the American Medical Association, 278, 1661.
Katz, W. (1996). Pharmacology and clinical experience with tramadol in osteoarthritis. Drugs, 52(3), 39-47.
Macdonald, R.L., & Kelly, K.M. (1994). Mechanisms of action of currently prescribed and newly developed antiepileptic drugs. Epilepsia, 35, S41.
Markovits, F., & Gilhar, A. (1997). Capsaicin: An effective topical treatment in pain. International Journal of Dermatology, 36, 401-404.
McQuay, H.J., Carroll, D., & Glynn, C.J. (1992). Low dose amitriptyline in the treatment of chronic pain. Anaesthesia, 47, 646-652.
McQuay, H.J., Carroll, D., Jadad, A.R., Glynn, C.J., Jack, T., Moore, R.A., & Wiffeh, P.J. (1994). Dextromethorphan for the treatment of neuropathic pain: A double-blind randomised controlled crossover trial with integral n-of-1 design. Pain, 59, 127-133.
McQuay, H., Carroll D., Jadad, A., Wiffeh, P., & Moore, A.(1995). Anticonvulsant drugs for management of pain: A systematic review. British Medical Journal, 311, 1047-1052.
Merren, M.D. (1998). Gabapentin for treatment of pain and tremor: A large case series. Southern Medical Journal, 91, 739-744.
Merskey, H., & Nogduk, N. (Eds.). (1994). Classification of chronic pain (2nd ed.). Seattle: IASP Press.
Meyer, R.A., Campbell, J.N., & Raja, S.N. (1994). Peripheral and neural mechanisms of nociception. In P.D. Wall & R. Melzack (Eds.), Textbook of pain (3rd ed., pp. 13-44.). New York: Churchill Livingstone.
Montauk, S.L., & Martin, J. (1997). Treating chronic pain. American Family Physician, 55(4), 451-460.
Nelson, K.A., Park, K., Robinovitz, E., Tsigos, C., & Max, M.B. (1997). High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology, 48, 1212-1218.
Onghena, P., & Van Houdenhove, B. (1992). Antidepressant induced analgesia in chronic nonmalignant pain: A meta-analysis of 39 placebo-controlled studies. Pain, 49, 205-219.
Price, D., Mao, J., Frenk, H., & Mayer, D. (1994). The N-methyl-D-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man. Pain, 59, 165-174.
Pujalte, J.M., Llavore, E.P., & Ylescupidez, F.R. (1980). Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthritis. Current Medical Research and Opinion, 7, 110-114.
Rani, P.U., Naidu, M.U.R., Prasad, V.B.N., Rao, T.R., & Shobah, J.C. (1996). An evaluation of antidepressants in rheumatic pain conditions. Anesthesia & Analgesia, 83, 371-375.
Rauck, R.L., Rouff, G.E., & McMillen, J.I. (1994). Comparison of tramadol and acetaminophen with codeine for long-term pain management in elderly patients. Current Therapeutic Research, 55, 1417-1431.
Reichell, L.A., Fonter, K.K., Rovati, L.C., & Setnikar, I. (1994). Efficacy and safety of intramuscular glucosamine sulfate on osteoarthritis of the knee. Arzneim-Forsch, 44, 75-80.
Saudek, C.D., Werns, S., & Reidenberg, M.M. (1977). Phenytoin in the treatment of diabetic symmetrical polyneuropathy. Clinical Pharmacology and Therapeutics, 22, 196-199.
Sindrup, S.H., Gram, L.F., Bronsen, K., Eshoj, O., & Morgensen, E.F. (1990). The selective serotonin uptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain, 42, 135-144.
Singh, L., Field, M., Ferris, P., Hunter, J.C., Oles, R.J. Williams, R.G., & Woodruff, G.N. (1996). The antiepileptic drug gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed by D-serine. Psychopharmacology, 127, 1-9.
Swinyard, E.A., Sofia, R.D., & Kupferberg, H.J. (1986). Comparative anticonvulsant activity and neurotoxicity of felbamate and four prototype antiepileptic drugs in mice and rats. Epilepsia, 27, 27.
Tandan, R., Lewis, G.A., Badger, G.B., & Fries, T.J. (1992). Topical capsaicin in painful diabetic neuropathy: Effect of sensory function. Diabetes Care, 15, 15-19.
Tandan, R., Lewis, G.A., Krusinsky, P.B., Badger, G.B., & Fries, T.J. (1992). Topical capsaicin in painful diabetic neuropathy: Controlled study with long-term follow-up. Diabetes Care, 15, 8-14.
Amy L. Whitaker is a community pharmacy practice resident, Daniel T. Kennedy is assistant professor, and Ralph E. Small is professor at the School of Pharmacy at Virginia Commonwealth University, Medical College of Virginia Campus, in Richmond, VA.