Methadone Analgesia in Cancer Pain Patients on Chronic Methadone Maintenance Therapy

Transcription

1 Vol. 21 No. 2 February 2001 Journal of Pain and Symptom Management 169 Clinical Note Methadone Analgesia in Cancer Pain Patients on Chronic Methadone Maintenance Therapy Paolo L. Manfredi, MD, Gilbert R. Gonzales, Andrea L. Cheville, Craig Kornick, MD and Richard Payne, MD Pain and Palliative Care Service, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Abstract Methadone is currently best known for its use as the maintenance drug in opioid addiction. The main concern when using methadone for the treatment of pain is its long and unpredictable half-life, which is associated with the risk of delayed toxicity. This may result in side effects such as sedation and respiratory depression if careful titration and close observation of individual patient responses are not performed. For this reason, methadone is often viewed as a second line opioid, after other opioids with a more predictable dose-response have been tried. We report six patients with long-term exposure to methadone as a treatment for heroin dependency, who were also treated with methadone for cancer pain. The first five patients were at least partially refractory to the analgesic effects of opioids other than methadone. All six patients achieved analgesia without sedation or respiratory depression from aggressive upward methadone titration. Methadone analgesia can be considered early in the course of treatment of patients with chronic exposure to methadone who develop new or worsening pain requiring opioid therapy. J Pain Symptom Manage 2001;21: U.S. Cancer Pain Relief Committee, Key Words Methadone, cancer, pain, opioid, addiction Introduction Methadone is a synthetic opioid currently best known for its use as the maintenance drug in opioid addiction. 1 Recent reports have underscored its efficacy in the treatment of cancer pain, especially for pain not controlled with high doses of Address reprint requests to: Paolo L. Manfredi, MD, Pain and Palliative Care Service, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY USA. Accepted for publication: April 4, other opioids. 2 5 The main concern when using methadone for the treatment of pain is its long and unpredictable half-life and the associated risk of delayed overdose 6,7 unless careful and individualized dose titration is undertaken. Varied strategies have been proposed to estimate safe and effective starting doses for methadone. 8 The need for close monitoring and individualized titration has been emphasized. 9 More data are needed to make definite recommendations and, at this time, methadone remains a second-line opioid in most institutions. This is true even in the population of patients maintained on methadone as a treatment for U.S. Cancer Pain Relief Committee, /01/$ see front matter Published by Elsevier, New York, New York PII S (00)

2 170 Manfredi et al. Vol. 21 No. 2 February 2001 heroin addiction. Experience with the use of methadone as an analgesic is particularly limited in this group. We report six patients with long-term exposure to methadone as a treatment of heroin dependency, who were referred to the pain management service of a cancer center and treated with methadone for cancer pain. Five of these six patients received other opioids for their cancer-related pain before receiving methadone. Cases Patient 1 A 43-year-old man with squamous cell cancer of the larynx had a history of heroin abuse and had been in a methadone maintenance program, at a stable dose of 60 mg per day, for ten years. His tumor progressed despite surgery and radiation therapy. Because of worsening pain in the neck and frontal area, he was treated with gradual increases in methadone up to 200 mg every 6 hours via gastrostomy tube (GT) over a 4-week period. Adding 10 mg of dexamethasone every six hours for two days did not help his pain, which remained at 6 on a 0 10 verbal numeric scale (NS). His opioid was rotated to intravenous (IV) hydromorphone and the dose was titrated up to 40 mg/hr with worsening pain (pain rated 8 on NS). He developed severe myoclonus and was hospitalized. His physical examination was remarkable for aphonia, right Horner s syndrome, a hard mass in the inframandibular and supramandibular regions on the right side, a right-sided neck fistula oozing small amounts of bloody fluid, tracheostomy, and gastrostomy tube. The opioid was rotated back to methadone IV and the dose was gradually titrated up to 70 mg/ hr. At this dose, the patient had no pain (0 on NS) but developed ringing in both ears and intermittent extensor spasms in the legs. The opioid was rotated to levorphanol with resolution of the above symptoms but recurrence of pain (7 on NS) at 40 mg/hr. The opioid was then rotated to morphine and the patient was discharged home at his request on a 50 mg/hr morphine infusion, with a pain score of 5 and significant sedation. When he lost his intravenous access, methadone was restarted via GT (250 mg/4hours) with better pain control (3 4 scores on NS) and no sedation within hours after the change. The pain remained under good control five weeks Fig. 1. Patient 1 opioid doses, routes, and days of treatment (y-axis: pain intensity). later on the same methadone dose. Figure 1 illustrates pain scores, opioid doses, routes and time course of treatment for this patient. Patient 2 A 38-year-old man with HIV disease (CD4 count of 48) and lymphoma involving the lumbar spine had a history of heroin abuse and had been in a methadone maintenance program, at a stable dose of 50 mg per day, for six years. The patient was complaining of excruciating pain in the lumbar region (10 on NS). The pain persisted despite a 400 g/hr transdermal fentanyl patch, oral methadone 50 mg once a day, and dexamethasone 6 mg every 6 hours for the past week. Fentanyl and methadone were stopped and IV morphine was started and titrated to 100 mg/hr. He still rated his pain as 10 on the NS and had not slept for two days because of pain, which worsened with sitting and recumbency. Hydromorphone was substituted and the dose was titrated up to 50 mg/hr over 24 hours without substantial changes in pain severity (9 on NS). His physical examination was remarkable for myoclonus, severe tenderness in the lumbar area with guarding of the area, loss of deep tendon reflexes in the legs, weakness in the anterior tibialis and gastrocnemius in the 3/5 range bilaterally, and a stocking distribution sensory loss. Hydromorphone was stopped and IV methadone was begun at 10 mg/hr with 10 mg boluses, as needed every hour. The patient was

3 Vol. 21 No. 2 February 2001 Methadone Maintenance in Cancer Patients 171 Fig. 2. Patient 2 opioid doses, routes, and days of treatment (y-axis: pain intensity). given three 10 mg boluses over the next five hours. He then went to sleep for the first time in three days and, upon awakening, 8 hours later, his pain was mild (3 on NS). The pain remained under good control on the same methadone dose until the patient expired in the hospital one week later. Figure 2 illustrates pain scores, opioid doses, routes, and time course of treatment for the second patient. Patient 3 A 55-year-old man presented with acute right arm pain after a minor trauma. He had a history of heroin abuse and had been maintained on a stable, oral methadone dose of 100 mg per day for twenty years. Radiographs revealed a humeral fracture at the site of a large lytic lesion involving almost the entire proximal humerus. An intramedullary rod was placed and a biopsy revealed a poorly differentiated neoplasm consistent with a giant cell tumor of the lung. Following surgical stabilization, the patient received palliative radiation therapy. Due to persistent pain worsened by movement of the right arm, he was started on oral controlled-release morphine at a dose of 30 mg twice daily, with oral 30 mg immediate-release morphine rescue doses every 4 hours as needed. His pain gradually escalated to an intensity of 10 on NS at rest, despite around-theclock use of his rescue doses. The patient was admitted to the hospital and IV morphine 30 mg every 3 hours was added to his methadone 100 mg/day without improvement. His pain score remained 8 10 on NS and a continuous morphine infusion was started at 10 mg/hr with 10 mg rescue doses every 15 minutes. In addition, his oral methadone dose was increased to 35 mg every 6 hours. On this regimen, the patient consistently rated his pain at 7 or higher at rest, and 10 with minimal movement of the right arm. The IV morphine dose was escalated to 160 mg/hr without improvement. Because of the lack of response to morphine, methadone was gradually increased as the morphine infusion was lowered. When the methadone dose reached 100 mg every 6 hours, and the morphine dose was reduced to 80 mg/hr, the pain improved dramatically and was rated by the patient as 0 2/10 on NS. The IV morphine was gradually tapered over 5 days and the pain remained well controlled on methadone alone until the patient expired 3 weeks later. Patient 4 A 34-year-old woman with poorly differentiated, recurrent squamous cell carcinoma of the cervix was treated with surgery, external beam radiation therapy, brachytherapy, and cisplatin chemotherapy. The patient had a history of heroin abuse and had been maintained on a stable oral methadone dose of 70 mg/day for twelve years. The patient presented with complaints of severe abdominal, suprapubic, lower back, and bilateral hip pain. She rated her pain as 10 on the NS for pain intensity. She was started on long-acting morphine, which was gradually increased to 1200 mg a day. She then received long-acting oxycodone, which was titrated to 3300 mg a day. In both instances, sedation occurred before significant pain relief. The opioid was then rotated to oral methadone 50 mg every six hours and the dose was escalated up to 70 mg every six hours after one week. At this dose, the pain was very well controlled (pain intensity on NS rated as 2) without opioid related side effects for over two months. Patient 5 A 45-year-old woman receiving chemotherapy and radiation therapy for recurrent breast cancer had a history of heroin abuse and had been maintained on a stable, daily, oral methadone dose of 20 mg for twenty years. She had

4 172 Manfredi et al. Vol. 21 No. 2 February 2001 chest wall pain due to malignant soft tissue invasion and was treated with 150 g/hr of transdermal fentanyl and oral hydromorphone 12 mg every 4 hours as needed, in addition to her daily 20 mg of methadone. This combination helped her pain for several months until the pain began to worsen as her local disease again progressed. Her dose was steadily escalated to control her worsening pain. When her pain intensity persisted at 8 on NS despite increasing the transdermal fentanyl to 500 g/hr and the oral hydromorphone to 20 mg orally every 2 hours, the opioid was rotated to long-acting morphine with morphine rescues. This regimen was escalated to 1000 mg of oral controlled release morphine every 8 hours with 120 mg of oral morphine rescues every 4 hours as needed, without improvement. The opioid was rotated to oral long-acting oxycodone 640 mg every 8 hours with morphine as needed; the pain worsened and the patient refused to continue this opioid. A rotation to methadone 70 mg every 8 hours provided good pain control (pain intensity of 3 on NS) in the absence of significant opioid-associated side effects for 4 weeks. Patient 6 A 40-year-old woman with recurrent laryngeal cancer despite treatment with surgery, radiation therapy, and chemotherapy had a history of heroin abuse and had been on a stable methadone maintenance dose of 90 mg/day for 20 years. Her physical examination was remarkable for aphonia, postsurgical and postradiation changes in the neck with allodynia triggered by light touch in the area of the sternocleidomastoid and the angle of the jaw bilaterally. Because of worsening neck pain, her methadone was increased to 50 mg every six hours with good analgesia and no side effects for two months. After two months, the pain worsened and her methadone dose was again increased, this time to 60 mg every 4 hours; oral choline magnesium trisalicylate and a topical local anesthetic were added to her analgesic regimen. The pain was under control for a month when she again required another methadone dose escalation, this time to 75 mg every 6 hours. Three months later, the methadone dose was again increased, this time to 85 mg every 6 hours, again with good response. Discussion Patients treated with methadone for opioid addiction who develop pain are customarily treated with a second opioid while the methadone maintenance dose is continued. This practice avoids the risk of increased pain associated with methadone withdrawal and also keeps the goals of therapy clear: should the pain resolve, the second opioid can be tapered. When new opioids were introduced for pain control in our patients, the methadone maintenance dose was stopped in Patient 1, initially continued and then stopped in Patient 2, and continued in the other patients. Methadone was discontinued in the first two patients because it was thought to be superfluous in the setting of aggressive IV titration with hydromorphone and morphine. Both of these patients experienced a severe pain crisis shortly after the discontinuation of methadone. When methadone is used as an analgesic, it needs to be administered in divided doses every 6 to 12 hours, rather than once a day as is customary in maintenance therapy for opioid addiction. This was the case in our patients, who received divided doses every 4 8 hours or continuous infusions. The first five patients were relatively refractory to the analgesic effects of opioids other than methadone and all six patients achieved rapid and long-lasting pain relief from methadone. Chronic methadone treatment may have an effect on opioid tolerance via different and apparently conflicting mechanisms leading to a similar end result: relative refractoriness to opioid analgesia from opioids other than methadone in patients on chronic methadone maintenance therapy. Exposure to methadone and its abrupt discontinuation cause changes at opioid receptors. There is experimental evidence that chronic treatment with methadone and not with morphine significantly increases the levels of G-protein-coupled receptor kinase Such a change could increase tolerance to the analgesic effect of other opioids in patients on chronic methadone maintenance therapy. Opioid tolerance may also be influenced by methadone via a mechanism involving the d-isomer. The d- and l- isomers of methadone s racemic mixture bind to the MK-801-labeled non-competitive site of the N-methyl-D-aspartate receptor (NMDA). 11 The NMDA receptor has been

5 Vol. 21 No. 2 February 2001 Methadone Maintenance in Cancer Patients 173 implicated in preventing central sensitization 12 and reversing opioid tolerance. 13 Discontinuation of methadone after chronic exposure, as was done in two of our six patients, will therefore end the NMDA antagonistic activity and potentially increase the analgesic tolerance to other opioids. Due to its very long half-life, residual drug rather than receptor changes could be directly interfering with the analgesic effects of other opioids days after discontinuation of methadone. Methadone is known to block the euphoric effects of heroin: 100 mg of oral methadone per day blocked the euphoria produced by 80 mg of IV heroin. 14 Levo-alpha-acetylmethadol (LAAM), a synthetic mu agonist structurally related to methadone but longer acting, produces a dose dependent block of subjective and objective effects of parenteral hydromorphone for up to 96 hours. 15 It is possible that, aside from euphoria, analgesia is also blocked by methadone and for this reason patients on methadone may be at least partially refractory to the effects of opioids other than methadone. The above mechanisms may help explain why both the abrupt discontinuation of methadone (loss of NMDA antagonism) or the continuation of the baseline methadone dose (G-protein-coupled receptor kinase 2 increase and blockage of opioid effects by methadone) may have caused our patients to be relatively refractory to the analgesic effects of opioids other than methadone. The reports of methadone-induced respiratory depression in cancer patients are limited to patients at the start of therapy 16,17 and do not involve patients already on methadone in whom the dose is escalated. Our first patient had symptoms of toxicity when methadone, in an attempt to control severe pain, was rapidly escalated to a very high dose. He experienced ringing in the ears and extensor spasms in the legs but did not develop sedation or respiratory depression. As the methadone dose was increased, no patient developed opioid-induced sedation or respiratory depression. Notwithstanding the need for an individualized and careful titration, the likelihood of a reduced risk of respiratory depression from methadone accumulation in these patients, compared to methadone naïve patients, should be noted. Another advantage of using methadone for cancer pain in patients with a history of opioid addiction relates to the risks of relapse into chemical dependence. It is well known that these risks need to be evaluated on an individual basis and are principally dependent upon the psychosocial milieu rather than the drug used. The main risk for these patients is more likely to be under-treatment, due to health care workers misconceptions, rather than relapse into chemical dependence. 18 Chemical dependence relapse did not pose a management problem in our patients, regardless of the opioid used. Nevertheless it is the impression of physicians experienced in the treatment of pain and opioid addiction that, in selected patients, both of these risks are less with methadone dose escalation compared to the introduction of another opioid. We acknowledge that other factors, independent of prior long-term methadone exposure, might be responsible for the superior effectiveness of methadone, compared with other opioids, seen in our patients. Individual variability in response to different opioids, 3 methadone s NMDA receptor activity 11 and its possible analgesic effects, the unique spectrum of methadone s activity at opioid receptor subtypes, 19 all might explain the superior efficacy of methadone, regardless of prior maintenance therapy. Further understanding of the implications of methadone s activity at the NMDA receptor and better delineation of opioid receptors and their heterogeneity might add insight to the poor analgesic response from opioids other than methadone seen in our patients. Efforts to understand the dramatic analgesic efficacy of methadone in some patients not responding to high doses of other analgesics will help identify patients or the medical conditions that contribute to a higher probability of responding to methadone rather than other opioids. Methadone should be considered early for the treatment of cancer pain in patients with chronic methadone exposure, such as patients on chronic methadone maintenance therapy. Should clinicians opt to use an opioid other than methadone as an analgesic in these patients, we suggest that methadone is continued, even if the doses of the new opioid are rapidly escalated, in order to avoid an exacerbation of pain as was seen in our first two patients.

6 174 Manfredi et al. Vol. 21 No. 2 February 2001 References 1. Gorman ES, Warfield CA. The use of opioids in the management of pain. Hosp Pract 1986;12:48A H. 2. Crews JC, Sweeney NJ, Denson DD. Clinical efficacy of methadone in patients refractory to other mu opioid receptor analgesics for the management of terminal cancer pain. Cancer 1993;72: Galer BS, Coyle N, Pasternak GW, Portenoy RK. Individual variability in the response to different opioids: report of five cases. Pain 1986;25: Manfredi PL, Borsook D, Chandler SW, Payne R. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain 1997;70: Morley JS, Watt JWG, Wells JC, et al. Methadone in pain uncontrolled by morphine. Lancet 1993; 342: Sawe J. High dose morphine and methadone in cancer patients. Clinical pharmacokinetic consideration of oral treatment (review). Clin Pharmacokinet 1986;11: Fainsinger R, Schoeller T, Bruera E. Methadone in the management of cancer pain: a review. Pain 1992;49: Ripamonti C, Groff L, Brunelli C, et al. Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin Onc 1998;16: Foley KM, Houde R. Methadone in cancer pain management: individualize dose and titrate to effect. J Clin Onc 1998;16: Ozaita A, Escriba PV, Ventayol P, et al. Regulation of G protein-coupled receptor kinase 2 in brains of opiate-treated rats and human opiateaddicts. J Neurochemistry 1998;70: Gorman AL, Elliott KJ, Inturrisi CE. The d- and l- isomers of methadone bind to the non-competitive sit on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett 1997;223: Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep nociceptive dorsal horn neurons following C fiber stimulation. Neuropharmacology 1987;26: Elliot K, Kest B, Man A, et al. N-Methyl-d-aspartate (NMDA) receptors, mu and kappa opioid tolerance, and perspectives on new analgesic drug developments. Neuropsychopharmacology 1995;13: Dole VP, Nyswander ME, Kreek MJ. Narcotic blockade. Arch Intern Med 1966;118: Houtsmuller EJ, Walsh SL, Schuh KJ, et al. Dose-response analysis of opioid cross-tolerance and withdrawal suppression during LAAM maintenance. J Pharm Exp Ther 1998;285: Symonds P. Methadone in the elderly. Br Med J 1977;1(6059) Ettinger DS, Vitale PJ, Trump DL. Important clinical and pharmacological considerations in the use of methadone in cancer patients. Cancer Treat Rep 1977;63: Gonzales GR, Coyle N. Treatment of cancer pain in a former opioid abuser: fears of the patient and staff and their influence on care. J Pain Symptom Manage 1992;7: Chang A, Emmel DW, Rossi GC, Pasternak, GW. Methadone analgesia in morphine-insensitive CXBK mice. Eur J Pharm 1998;351: