PHARMACY PERSPECTIVE Methadone for cancer-related neuropathic pain: A review of the literature Rosemarie Mannino, MD Patrick Coyne, MSN, APRN Craig Swainey, MD Lea Ann Hansen, PharmD Laurie Lyckholm, MD AbSTRACT nEuRoPATHIC PAIn In CAnCER Neuropathic pain is commonly seen in cancer patients, Clinical presentation either as a direct result of the malignancy or as a conse - quence of the treatment rendered. In recent years, Persons with cancer often experience several different methadone has been utilized in the treatment of neuro - types of pain simultaneously, making neuropathic pain pathic pain because of its additional mechanism of difficult to distinguish from somatic and visceral pain. action as an NMDA-receptor antagonist. In this paper Various malignant processes—for example, vertebral we discuss the etiology of neuropathic pain in cancer invasion with nerve compression—may present as both patients, unique properties of methadone, and prior somatic and neuropathic pain. stud ies on methadone in this patient population. While Neuropathic pain can be defined as pain related to methadone has been established as a cheap and effective abnormal somatosensory processing in either the periph - agent in treating cancer pain, specific studies are needed eral or central nervous system. 3 It may come to exist inde - comparing methadone to other opioids in the manage - pendently of any initial injury or damage, resulting in a ment of cancer-related neuropathic pain. state of persistent pain, 4 and it can occur at any time dur - Key words: neuropathic pain, NMDA receptors, ing the person’s life. In an international survey of 1,095 methadone, morphine consecutive cancer patients with severe pain, 40 percent reported a neuropathic component. 5 Descriptions of neuropathic pain include burning, InTRoduCTIon electric shock, tingling, pricking, itching, cold, aching, numbness, tenderness, pulling, tugging, penetrating, Pain and symptom management are an integral part of punishing, miserable, and nagging, and the sensations cancer management. 1,2 Neuropathic pain is commonly can be associated with neurologic deficits. 6,7 Patients seen in cancer as a result of either the treatment or the with neuropathic pain may complain of spontaneous cancer itself. Because of its mechanism of action, and/or evoked pain. Spontaneous pain, due to sudden, methadone is thought by many pain and palliative medi - unprovoked firing of axons or dorsal horn neurons, can cine specialists to be more effective than other opioids in present as paroxysmal lancinating pain, as constant the treatment of neuropathic pain. No specific agent has burning pain, or as a cramping or aching sensation. been identified as the preferred or clearly superior treat - Evoked pain, caused by damage or alterations to ment of neuropathic pain, but morphine remains the gold peripheral and central sensory neurons, can present as standard for the treatment of cancer pain. A first-line hyperalgesia (lowered threshold to painful stimuli), agent should be identified in order to standardize care, allodynia (pain from normally innocuous stimuli, such and methadone may be a candidate for this distinction. In as light touch), and hyperpathia (increased pain from a this article, the causes of neuropathic pain in cancer are normally painful stimulus). 4 It can be elusive and resist - reviewed, as well as the literature regarding the use of ant to many types of analgesics, making it a challenge methadone for neuropathic pain in cancer patients. to treat. 8,9 Journal of Opioid Management 2:5 n September/October 2006 269 Causes Phantom limb pain is reported to occur in as many as 66 percent of patients within the first six months after ampu - The etiology of neuropathic pain in cancer patients tation. In 5 to 10 percent of patients the pain is severe, can be a direct result of the malignant disease (compres - persistent, and often resistant to conventional therapy sion of a nerve or nerve plexus) or a consequence of with drugs. 15 Phantom breast pain after mastectomy, treatments such as radiation, surgery, and/or chemother - which appears to be related to preexisting preoperative apy. 10,11 Radiation-induced plexopathies are most often pain, can occur in 15 to 30 percent of patients. 16 There is described as occurring in the brachial or lumbosacral postulation that transmission of noxious afferent input to plexus. They include three distinct clinical syndromes: the spinal cord from a peripheral injury causes a central reversible or transient plexopathy; classic delayed, pro - neural sensitization, amplifying subsequent input. 17,18 gressive radiation injury with fibrosis; and acute ischemic Chemotherapy-induced peripheral neuropathy has plexopathy. Transient brachial plexopathy occurs during been a significant dose-limiting toxicity, as detailed in a or within a few months of finishing radiation treatment; it 1999 review by Windebank. 19 In general, there is a pre - results when an external beam’s field has included the disposition to neuropathy in patients with prior nerve brachial plexus, and it usually resolves with time. Most damage from conditions such as diabetes, heavy alcohol often this occurs in women with early breast cancer who use, or inherited neuropathy. 20 Classes of agents causing are receiving radiation after conservative surgical treat - neuropathy include platinum-containing compounds (cis - ment. Symptoms include numbness in the thumb and platin and oxaliplatin), taxanes (paclitaxel and docetaxel), first finger of the affected side and weakness in the shoul - and the vinc a alkaloids (vincristine and vinblastine). 16 der and biceps muscles. 12 With cisplatin, DNA synthesis is impaired as a result of The pathogenesis of radiation-induced plexopathy is platinum binding to DNA, thereby producing inter- and unknown and symptoms may resolve spontaneously intrastrand crosslinks. 21 The neurotoxicity of cisplatin and within weeks or months. Late delayed brachial plexopa - oxaliplatin manifests as pure sensory involvement, is thy occurs months to years following axillary or supra - related to cumulative dosing, and can progress for weeks clavicular radiation. Observation-based evidence sug - despite discontinuation of the drug. 22 Cisplatin is postu - gests that damage stems primarily from vasculitis lated to cause neuronal apoptosis by an unknown mech - resulting in sclerotic occlusion of small supplying vessels, anism. Oxaliplatin appears to interfere with neural or demyelination and fibrosis within and surrounding excitability and axonal ion conductance, resulting in neu - nerves in the radiation field. Paresthesias, hypesthesias, rotoxicity. 21 weakness, and impaired reflexes may occur. 12 The taxanes and vinca alkaloids interfere with micro - Chronic post-thoracotomy pain syndrome occurs in 44 tubule-based axonal transport, thereby causing axonal to 67 percent of patients after thoracotomy, most com - injury that leads mainly to sensory loss. Paresthesias of monly from recurrent or persistent tumor in the distribu - the hands and feet are frequently the initial manifestation tion of the thoracotomy. It is defined as pain persisting of neuropathy from these compounds. Unfortunately, along the thoracotomy scar longer than two months post - these paresthesias can interfere with activities of daily liv - operatively. It usually involves moderate or severe pain ing such as buttoning one’s shirt or using a car’s gas and in the distribution of one or more intercostal nerves, and brake pedals. The neuropathies associated with these the duration of pain appears to be longer in patients with agents tend to resolve in the months following their dis - malignancy. The most severe pain in the syndrome, continuation, though not in all cases. Chemotherapy- occurring in approximately 3 percent of patients, appears induced central neurotoxicity may also be caused by to be due to intercostal neuralgia. The exact mechanism methotrexate, cytarabine, and ifosfamide. Acute aseptic is unclear. 13 meningitis and delayed neurotoxicity including cognitive Postmastectomy pain syndrome (PMPS) is a chronic impairment, aphasia, progressive dementia, and hemi - pain condition that was first reported in the 1970s. It is paresis have been described. Risk factors include higher typically neuropathic in nature and can occur following doses of the agents, frequent administration, and radia - surgery on the breast. PMPS is described as a dull, burn - tion preceding methotrexate dosing. 21 ing, and aching sensation in the anterior chest, arm, and axilla, exacerbated by movement of the shoulder girdle. MAnAgIng nEuRoPATHIC PAIn The etiology of PMPS is unclear, but theories have been postulated implicating dissection of the intercosto - opioids brachial nerve, intraoperative damage to axillary nerve pathways, and/or pain caused by neuroma. 14 Opioids are considered a cornerstone in the manage - Phantom pain originates from a missing body part ment of neuropathic pain. 22 Two studies by Watson and (such as a limb or breast) and may exacerbate already colleagues 23,24 addressed this issue in randomized, dou - disabling conditions, especially in patients with cancer. ble-blinded trials using controlled-release oxycodone. 270 Journal of Opioid Management 2:5 n September/October 2006 One trial enlisted patients with postherpetic neuralgia, Table 1. Proposed methadone-to-morphine and the subsequent trial involved patients with painful conversion ratios diabetic neuropathy. Both trials concluded that con - trolled-release oxycodone