Current Pharmacotherapy of Chronic Pain

S16 Journal of Pain and Symptom Management Vol. 19 No. 1(Suppl.) January 2000 Proceedings Supplement NMDA-Receptor Antagonists: Evolving Role in Analgesia Current Pharmacotherapy of Chronic Pain Russell K. Portenoy, MD Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, New York, USA Abstract Advances in basic and clinical research have greatly expanded the options for analgesic pharmacotherapy. There are three broad categories of analgesic medications: (1) nonopioid analgesics, which includes the nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, dipyrone, and others; (2) a diverse group of drugs known as the adjuvant analgesics, which are defined as drugs that have primary indications other than pain but may be analgesic in selected circumstances; and (3) opioid analgesics. The advent of highly selective COX-2 inhibitors has generated excitement because of the possibility that these new NSAIDs will be much safer than previous COX inhibitors. However, the cost benefit of using these relatively more expensive drugs versus other NSAIDs plus gastroprotective therapies needs to be determined. Adjuvant analgesics can be grouped into four major classes according to their use: multipurpose, neuropathic pain, musculoskeletal pain, and cancer pain. There has been a dramatic increase in the number of these drugs during the past two decades and they now play an important role in the management of chronic pain. Pain specialists are now using opioids for chronic nonmalignant pain in addition to the traditional use for acute and cancer pain. This change in practice evolved from recognition that selected patients with chronic noncancer-related pain can experience sustained analgesia and function better with these drugs, without developing an addictive disorder. The combination of opioids and other drugs, such as an N-methyl-D-aspartate-receptor antagonist, may improve the balance between analgesia and adverse effects. J Pain Symptom Manage 2000;19:S16 S20. U.S. Cancer Pain Relief Committee, 2000. Introduction Rapid advances in basic and clinical research have greatly expanded the options for analgesic pharmacotherapy. This has been most important for the extremely large and diverse population with chronic pain. For some patients with chronic pain, such as those with cancer pain, analgesic drug therapy is the Address reprint requests to: Russell K. Portenoy, MD, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, New York, 10003, USA. Accepted for publication: September 17, 1999. mainstay approach and may be appropriately used as a single strategy. In other types of patients, drug therapy is one element in a multimodality strategy. Regardless, the optimal use of analgesic drugs is now an essential goal of pain management. Pharmacotherapy involves three broad categories of analgesic medications. The nonopioid analgesics include the nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen, and others that are not available in the United States. A very broad and diverse group of drugs is known as the adjuvant analgesics. These drugs have primary indications other than pain, but may be analgesic in selected circum- U.S. Cancer Pain Relief Committee, 2000 0885-3924/00/$ see front matter Published by Elsevier, New York, New York PII S0885-3924(99)00124-4

Vol. 19 No. 1(Suppl.) January 2000 Current Analgesic Pharmacotherapy S17 stances. The third category includes opioid analgesics. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) The mechanism of the NSAIDs is to inhibit both peripheral and central cyclooxygenase. There are two main forms of cyclooxygenase: COX-1, which is constitutive (that is, the compounds produced by the activity of this enzyme are necessary for normal physiologic function of stomach, kidney, and platelets), and COX-2, which is inducible and involved in inflammation. It has long been recognized that the possibility of selectively inhibiting COX-2, while leaving COX-1 uninhibited, may produce an NSAID with a greater therapeutic index. Nonselective COX inhibitors have been available for many years and now include numerous drugs in diverse classes: salicylates, propionic acids, acetic acids, oxicams, naphthylalkalones, and fenamates. The relative selectivity between COX-1 and COX-2 varies across these agents, and drug-specific differences in toxicity are in part based on this relative selectivity. The advent of highly-selective COX-2 inhibitors, such as celecoxib (Celebrex) and rofecoxib (Vioxx), has generated great excitement because of the possibility that these highly-selective COX-2 inhibitors will actually be much safer than nonselective COX inhibitors, even those that are more selective for COX-2 than for COX-1. NSAIDs have dose-dependent effects. The ceiling dose for analgesic and anti-inflammatory effects has been evaluated in broad terms in dose-ranging studies, but, in any individual patient, the minimum effective dose and ceiling dose are unknown. This suggests the value of dose titration. All these drugs are nonspecific analgesics and can be effective for a variety of pain syndromes. They produce no physical dependence or tolerance. There is marked individual variation in analgesic efficacy and side effects, and the concept of sequential drug trials or drug rotation has been accepted for a long time. Despite considerable knowledge about the basic mechanisms of NSAIDs and information from numerous clinical studies, guidelines regarding NSAID selection and dosing are empirical, based on best clinical judgment. It is generally better to titrate from a low dose, particularly among patients who are relatively predisposed to toxicity. As the dose is increased, there is the need to recognize the ceiling effect. The potential for adverse effects must be recognized. Unfortunately, most of the toxicities with these drugs are actually occult. For example, the risk of massive GI hemorrhage increases with dose, but one cannot predict that risk; the first sign is frequently when the patient presents with a life-threatening hemorrhage. To reduce the risks associated with these drugs, clinicians must recognize the high-risk patients (e.g., the elderly; those receiving corticosteroids or anticoagulants; those who have previously experienced NSAID toxicity; etc.), use the safest agents possible, and try to identify the minimal effective dose. It is important to recognize improvements in gastroprotective therapy that have been evaluated with the nonselective COX drugs. Prostaglandin analogues (e.g., misoprostol), proton pump inhibitors (e.g., omeprazole), and H2 blockers (e.g., famotidine) have been shown to be effective. The advent of the selective COX-2 inhibitors offers great clinical potential. However, the cost benefit of using these relatively more expensive drugs compared to nonselective NSAIDs with gastroprotective therapies is unknown. In populations not at high risk for GI hemorrhage, for example, it may be just as beneficial to use ibuprofen and an inexpensive H2 blocker, rather than a COX-2 selective inhibitor, which incurs a higher cost for the patient. This kind of information needs to be determined and made available. Adjuvant Analgesics Advances in NSAID therapy pale in comparison to the enormous advances that have occurred in the area of adjuvant analgesics over the past 20 years. 1 It has been astounding to see the development of data supporting the use of a broad array of drugs that were hitherto thought to be nonanalgesic. Adjuvant analgesics can be grouped into four major classes according to their use. For example, drugs that can potentially work for any kind of pain are classified as multipurpose analgesics. Some drugs are used for neuropathic pain, some are used predominantly for

S18 Portenoy Vol. 19 No. 1(Suppl.) January 2000 Table 1 Adjuvant Analgesics: Major Classes Multipurpose analgesics Neuropathic pain Musculoskeletal pain Cancer pain Antidepressants 2 -adrenergic agonists Corticosteroids Local anesthetics Anticonvulsants GABA agonists Neuroleptics Topical analgesics Calcitonin Sympatholytics Muscle relaxants Some benzodiazepines Osteoclast inhibitors Radiopharmaceuticals Anticholinergics Octreotide musculoskeletal pain, and some are used predominantly or exclusively in the cancer pain population (Table 1). Multipurpose Analgesics Among the multipurpose analgesics are antidepressants, 2 -adrenergic agonists, and corticosteroids. The importance of antidepressant analgesia has been recognized for decades. These widely used drugs can potentially help chronic pain of any type, as indicated by controlled clinical trials in a variety of diverse pain syndromes. If used for neuropathic pain, they have traditionally been preferred for continuous dysesthesia, and are second-line for lancinating dysesthesia. Most of the data supporting these drugs as analgesics were evaluated for the tricyclic antidepressants. Some studies have compared the relatively more toxic, tertiary amine drugs, such as amitriptyline, against the secondary amine drugs like desipramine. However, there are few studies that have compared those drugs against the even safer compounds, the serotonin selective reuptake inhibitors (SSRIs) and the atypical antidepressants, e.g., venlafaxine (Effexor ). Because there is little information, the selection of drugs at this point is in the realm of good clinical judgment. Drug selection must be based on a careful evaluation of the patient, which may suggest a specific drug or give the clinician a sense of whether the patient will be able to tolerate a tricyclic versus a selective serotonin reuptake inhibitor. Considerably more information is needed to be able to select a specific antidepressant on the basis of predicted efficacy or tolerability. The 2 -adrenergic agonists also are multipurpose analgesics. In the United States, there are now two drugs available, clonidine (Catapres ) and tizanidine (Zanaflex ). Tizanidine, which has been on the market for a relatively short period of time, may be better tolerated than clonidine. These drugs can potentially be used for patients with syndromes as diverse as headache, lower back pain, neuropathic pain, and cancer pain. Drugs for Neuropathic Pain For the treatment of neuropathic pain, the antidepressants and 2 -adrenergic agonists can be used. In addition, a large number of drugs have been targeted specifically for neuropathic pain. One could speculate that these drugs actually might be multipurpose analgesics, but the data do not allow a recommendation for use in any type of pain syndrome other than neuropathic pain. The most popular drug by far is gabapentin (Neurontin ), an anticonvulsant. In the last year or so, two placebo-controlled randomized trials have demonstrated the analgesic efficacy of gabapentin in postherpetic neuralgia and diabetic painful polyneuropathy. In these trials, the dose was titrated as high as 3600 mg. To maximize the benefits of this drug, gradual dose escalation to this level, and sometimes even higher, may be needed. Other anticonvulsants have been used for pain for many years, but in general, studies have established analgesic efficacy only for patients with lancinating or paroxysmal dysesthesia. Empirically, however, some patients with continuous dysesthesias who have been treated with anticonvulsant therapy have done extremely well. Carbamazepine (Tegretol ), phenytoin (Dilantin ), valproate (Depakote ), clonazepam (Klonopin ), as well as newer drugs, such as lamotrigine (Lamictal ), topiramate (Topamax ), and tiagabine (Gabatril ) are on the list of anticonvulsant drugs that are tried, sometimes sequentially, in patients with refractory neuropathic pain. This is a remarkable demonstration of how quickly the area of adjuvant analgesics is evolving. Oral local anesthetics, such as mexiletine (Mexitil ), flecainide (Tambocor ), or tocainide (Tonocarel ), are also used for chronic neu-

Vol. 19 No. 1(Suppl.) January 2000 Current Analgesic Pharmacotherapy S19 ropathic pain of any type. In the United States, mexiletine is generally preferred. Neuropathic pain and other types of pain syndromes also can be treated with topical analgesics. Local anesthetics typically do not penetrate the epidermis and produce cutaneous anesthesia, but EMLA cream, a eutectic mixture of local anesthetics (i.e., 1:1 mixture of prilocaine and lidocaine), does penetrate epidermis and can produce anesthesia. The Food and Drug Administration has just approved a new topical local anesthetic, lidocaine (Lidoderm ), a patch for use in postherpetic neuralgia that may be a useful addition to local anesthetic therapies. The analgesic efficacy of topical capsaicin continues to be controversial. The best studies seem to be those in patients with painful, small joint osteoarthropathy, and not neuropathic pain syndromes. This drug is relatively safe and is often tried. Topical NSAIDs are effective analgesics in some patients. In the United States, topical NSAIDs, other than topical salicylates, have not made it to the marketplace, but some pharmacies will compound these products for clinicians. This may be another way of approaching different types of pain, including neuropathic pain. N-methyl-d-aspartate (NMDA)-receptor antagonists reflect a new approach in the broad category of adjuvant analgesics. Preclinical studies have established that this receptor is involved both in the development of neuropathic pain and in the appearance of opioid tolerance. Studies in experimental pain and clinical pain have confirmed the potential for analgesics from NMDA-receptor blockers. New data also confirm the capacity for analgesic potentiation when such a drug is added to morphine. The broad utility of NMDA-receptor antagonists as single-entity analgesics and as analgesics in combination with other drugs, such as the opioids, is discussed elsewhere in this supplement. Drugs for Musculoskeletal Pain There is very little evidence that the most popular muscle relaxant drugs, such as orphenadrine (Norflex ), methocarbamol (Robaxin ), carisoprodol (Soma ), chlorzoxazone (Parafon Forte ), cyclobenzaprine (Flexeril ), or metaxalone (Skelaxin ) actually relax skeletal muscle. Nonetheless, when these drugs are studied in acute dosing paradigms in patients with musculoskeletal pain, they are effective analgesics. Their sedative and anticholinergic side effects are usually well tolerated, particularly with acute doses, and they are commonly used for acute musculoskeletal pain. Opioids There has been a dramatic change in the way pain specialists view the use of opioid drugs for the management of chronic, noncancer-related pain. 2 It has been accepted for decades that opioid analgesics are the mainstay approach for acute pain and chronic cancer pain. Their role in chronic nonmalignant pain is rapidly evolving. The traditional view is that opioids should not be used for chronic nonmalignant pain because of side effects, tolerance, and addiction. Data generated from multidisciplinary pain management programs about 10 years ago suggested that opioid use was associated with more pain, more disability, more distress, less effective therapy, and substance abuse behavior. These data, however, cannot be generalized to the entire pain population. The strong referral bias and observer bias that exist in multidisciplinary pain management programs do not reflect the reality of clinical practice. There is growing recognition that selected patients with chronic noncancer-related pain can be provided opioid drugs for prolonged periods without overt evidence of tolerance and without intolerable toxicity. Many patients function better with these drugs. These observations have led to the development of consensus statements in support of cautious opioid use in carefully selected and well-monitored patients. These consensus statements have now been published by the American Pain Society, American Academy of Pain Medicine, American Society of Addiction Medicine, and the Canadian Pain Society. This evolving view of opioid therapy is supported by data from surveys and controlled studies. The latest controlled study, 3 a randomized, long-term comparison of two opioid regimens and naproxen in patients with low back pain, demonstrated less pain and less emotional distress among opioid-treated patients. Patients with diverse pain states could potentially benefit from opioid therapy. Serious adverse effects are rare, and doses generally re-

S20 Portenoy Vol. 19 No. 1(Suppl.) January 2000 main stable, if the pain syndrome is stable. Addiction (defined as loss of control over the drug, compulsive drug use, and continued use of the drug despite harm) is rare, particularly if there is no history of chemical dependency. A therapeutic opioid trial may be warranted in selected patients. Future research needs to provide more information about the clinical use of these drugs: how to select patients; how to select the right drug; how to titrate the drug; how to manage side effects; how to appropriately monitor the outcomes in chronic nonmalignant pain, including outcomes related to chemical dependency; and finally, how to add drugs to the opioids to maximize benefit and minimize risk by improving the balance between analgesia and adverse effects. The goal is to improve maximal efficacy and the ease of therapy. References 1. Portenoy RK. Adjuvant analgesics. In: Doyle D, Hanks GW, MacDonald RN, eds. Oxford textbook of palliative medicine, 2nd ed. Oxford, UK: Oxford University Press, 1998:361 389. 2. Portenoy RK. Opioid therapy for nonmalignant pain: a clinician s perspective. J Law Med Ethics 1996;24:296 309. 3. Jamison RN, Raymond SA, Slawsby EA, et al. Opioid therapy for chronic noncancer back pain: a randomized prospective study. Spine 1998;23:2591 2600.