sign in sign up
<<
Home , Peripheral neuropathy

Reviews/Commentaries/ADA Statements COMMENTARY

Use of for the Treatment of

LEWIS HAYS, MD, MPH MICHELLE DORAN, APRN, BC-PCM property, methadone, in theory, appears COLEEN REID, MD KARYN GEARY, APRN, BC-PCM to be the ideal for neuropathic and may account for the demonstration that the need for opioid escalation was significantly less in patients treated for pain with methadone than in those Editor’s comment: This is the second Commentary of those that will appear from time to time describing treated with (7,9). treatments that may not have been validated by appropriate clinical trials but seem to be effective in 2). Inhibition of the reuptake of nor- diabetic patients based on small studies and/or extensive clinical experience. This one describes effective epinephrine and serotonin. Facilitates im- opioid treatment for those diabetic patients failing nonopioid therapies for painful neuropathy. proved analgesia in . Care 28:485–487, 2005 Tricyclic antidepressants have traditionally been used to accomplish this task (2,10). 3). Trimodal metabolism/excretion. Metabolism in the liver via the cyto- ethadone, a schedule II opioid, to be more opioid responsive than those chrome P-450 system, fecal, and, to a was developed in Germany in the with pain from central le- lesser extent, renal excretion (other opi- M 1940s as a spasmolytic and was sions (5). Of the more than 2 million oids are excreted renally) (1). not used as an analgesic agent until many Americans affected by chronic neuro- 4). No active metabolites. This de- years later. In the 1960s, methadone was pathic pain, a significant subset is com- creases the incidence of side effects such researched and tested as a medical treat- prised of individuals with diabetic as confusion, sedation, myoclonus, sei- ment for the growing crisis of heroin ad- . In a small report, zures, and a variety of other adverse reac- diction and since then has been primarily Bergmans et al. (6) concluded that meth- tions related to build up of toxic used as a to prevent with- adone may be of particular value in the metabolites (1). drawal in drug-addicted patients. In treatment of pain and ad- 5). Highly lipophilic. Leads to excel- 1976, the American Pharmaceutical Asso- vocated for controlled clinical trials to lent absorption, rapid crossing over of the ciation won a suit allowing providers to verify their observations. blood-brain barrier, and marked drug dis- dispense methadone as an analgesic Methadone, a potent ␮ (mu) agonist, tribution in both muscle and fat, leading to agent. Since that time, any provider with a has a number of unique properties that we high bioavailability (considered to be about schedule II license can prescribe metha- feel, based on our clinical experience, three times that of other oral opiods). This done for the treatment of pain (1). Twen- make it the first line “opioid of choice” for allows methadone to be administered ty-eight years later, there continues to be the treatment of persistent neuropathic orally, in liquid and tablet form, as well as little literature on the use of this analgesic pain. Fishman et al. (7) noted that “ad- rectally, intravenously, epidural, intrathe- agent and methadone continues to be ministering methadone to opioid naı¨ve cally, and subcutaneously (1,11). Among rarely prescribed, if at all, by most health individuals may possess a greater margin the long-acting , only methadone is care providers. of safety than after exposure to other opi- available as a liquid and can be given sub- In her New England Journal of Medicine oids” and that “methadone may be better lingually (concentrate) or via a g-tube. editorial, Foley (2) emphasized that as a first-line opioid than as a traditional Methadone works both as a sustained- “given our lack of data about how to man- second or third line choice.” The proper- release and immediate-acting medication. age chronic neuropathic pain, we must ties of methadone that set it apart from With chronic dosing, methadone analgesia focus urgent attention on the needs of suf- other opioids include the following. lasts an average of approximately 10 h (12). fering patients.” It has been recognized 1). Antagonism to NMDA (N-methyl- Upon acute administration, analgesia be- that a main indication for methadone use D-aspartate) receptors, known modula- gins within 20 min and peaks in 3–4.5 h, in palliative medicine is the treatment of tors of neuropathic pain and important in allowing it to be used for breakthrough neuropathic pain. Two small studies (3,4) the attenuation of the development of have demonstrated the analgesic efficacy morphine tolerance (1). NMDA is an ex- pain, and a single dose lasts 4–6 h (12). of methadone in the treatment of neuro- citatory amino acid that has been impli- 6). Very inexpensive. Methadone is pathic pain. One study demonstrated that cated in the development of neuropathic available only as a generic agent, making patients with peripheral neuropathy seem pain and opioid tolerance (8). Due to this it very inexpensive when compared with the cost of all the newer brand name long- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● acting opioids and nonopioids used in From the Hospice of the North Shore and Palliative Care Consult Service, Danvers, Massachusetts. treating pain. Address correspondence and reprint requests to Lewis Hays, MD, MPH, Palliative Care Consult Service of The combination of trimodal elimina- Hospice of the North Shore, 10 Elm St., Danvers, MA 01923. E-mail: [email protected]. Received for publication 16 July 2004 and accepted in revised form 20 October 2004. tion and absence of active metabolites Abbreviations: HNS, Hospice of the North Shore. translates clinically to the fact that meth- © 2005 by the American Diabetes Association. adone dosing does not have to be adjusted

DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005 485 Commentary

Table 1—Daily oral morphine dose equiva- breakthrough pain dosing should be at Case example lents followed by the conversion ratio of oral least 10–20% of the total daily dosage, Charlie is a 74-year-old male with a com- morphine to oral methadone given every 3–4 h as needed. Dosing does plex medical history that includes type 2 Ͻ100 mg 3:1 not need to be symmetric, and since the diabetes, coronary artery disease, chronic (i.e., 3 mg morphine:1 pain of diabetic neuropathy oftentimes renal insufficiency, and advanced chronic mg methadone) worsens at night, we frequently give a obstructive pulmonary disease. He lived 101–300 mg 5:1 larger dose at bedtime or at any other time independently at home but was experi- 301–600 mg 10:1 of the day when pain tends to increase, encing progressive difficulty performing 601–800 mg 12:1 such as when individuals are up and activities of daily living due to his bilateral 801–1,000 mg 15:1 about. Titration of the scheduled doses foot pain. He described his pain as persis- Ͼ1,001 mg 20:1 may occur every 4–7 days, as needed, de- tent burning pain that “felt like fire.” It pending on the analgesic response and re- was exacerbated by prolonged standing, Due to incomplete cross-tolerance, it is recom- mended that the initial dose be 50–75% of the equi- quirements for breakthrough dosing, got worse late in the day, and was some- analgesic dose (1). with the scheduled doses titrated up to what improved with rest and elevation. reflect the total dose of methadone re- He rated this pain as 5 of 10 at best and 10 ceived over 24 h (scheduled plus break- of 10 at worst. Based on the description of in the face of renal insufficiency/failure. through doses). Occasionally, we will his pain, his long-standing diabetes, and his This gives methadone another very dis- need to select 6-h dosing in those few pa- physical exam, which demonstrated the tinct advantage over the other opioids in tients who do not get a full 8 h of analgesia classic findings of peripheral neuropathy, the treatment of the neuropathy com- from their scheduled methadone doses. i.e., decreased light touch and pinprick in a monly seen in dialysis patients, many of As the total daily opioid dose increases, stocking-glove distribution, the diagnosis of whom have diabetes and diabetic neurop- the breakthrough dose should also be in- diabetic peripheral neuropathy was made. athy but some of whom have neuropathy creased to remain at ϳ10–20% of the to- The Palliative Care Team of HNS was con- exclusively on the basis of their renal fail- tal daily dose. sulted to help manage his pain after multi- ure. This fact lends support to the argu- When converting a patient from an- ple analgesic regimens/combinations, ment that methadone should be strongly other opioid to methadone, the clinician including SR, oxycodone IR, considered for use as the first-line opioid should first convert the current opioid to , amitryptyline, and transdermal analgesic for treatment of neuropathy, morphine-equivalent doses using an , were unsuccessful in subduing particularly in the face of chronic renal equianalgesic table. The current mor- the pain. He took various other medica- insufficiency (1). phine equivalent dose then needs to be tions, including inhalers, aspirin, pred- Hospice of the North Shore (HNS) converted to methadone using a metha- nisone, lisinopril, and senna. His opioid and the Palliative Care Consult Service of done conversion table. It is also important analgesic regimen was converted from 25 HNS have treated large numbers of pa- to reduce the initial starting dose of meth- ␮g fentanyl to 2.5 mg methadone every 8 h tients successfully and gained significant adone by ϳ25–50% because cross- and 2.5 mg q3h prn. Four days after meth- clinical experience in using methadone in tolerance to the new opioid may be adone was initiated, the patient noted that the treatment of persistent neuropathic incomplete. Table 1 is the conversion ta- he needed an average of one breakthrough pain, with particular success in treating ble used by our team. dose per day and felt more alert. After 10 diabetic neuropathy. Much of the time, Side effects are generally less com- days, the methadone dose was changed to 5 we will recommend starting with adju- mon and less severe in association with mg b.i.d. with 2.5 mg q3h prn. He was able vants, such as gabapentin and/or tricyclic methadone use when compared with to optimally perform his activities of daily antidepressants, for those patients with other opioids. If the side effects that de- living, was sleeping better, and noted that mild pain (1–3 on 0–10 scale) from dia- velop are significant, we recommend dose his breathing had improved. He did not ex- betic peripheral neuropathy who have not reductions of ϳ25% (usually withhold- perience sedation, had less , had trials on these . For those ing a single daily dose if the patient is and was able to discontinue his bedtime patients already being treated with adju- receiving their methadone every 8 h). If Gabapentin. His clinical status has re- vants, we will evaluate the current dose and, the side effects are just undesirable, we mained unchanged for months now. if subtherapeutic, will maximize the doses recommend closely observing the patient, In conclusion, it has been our clinical and reassess the response. For patients since they will usually resolve within a experience that methadone is a unique whose pain is moderate to severe (Ն4on few days. Constipation, the most com- opioid analgesic that we have found to 0–10 scale), and who are symptomatic de- mon side effect of any opioid, needs to be provide consistently superior analgesia spite maximizing the adjuvant medication, managed with an aggressive bowel regi- for the treatment of diabetic neuropathy/ we will initiate methadone if they are opioid men. Other side effects associated with persistent neuropathic pain, when com- naı¨ve or, if they are on an opioid other than methadone use include , , pared with the other opioids currently methadone, we will convert their currently sweating, pruritus, and, rarely, respira- available, without sacrificing safety or tol- prescribed opioid to methadone. tory depression. Discontinuation of erability. Our initial therapy for diabetic Opioid-naı¨ve, frail, or elderly patients methadone should be carried out similar peripheral neuropathy still includes the are initiated on low doses: 0.5–1 mg every to stopping any long-acting opioid, with a use of tricyclic antidepressants, anticonvul- 8 h; the general population is started on slow taper over a period of days to weeks sants, or combinations of those drugs. 2.5–5 mg every 8 h. Breakthrough pain to prevent withdrawal symptoms and ces- However, when we do not get an adequate can also be treated with methadone, and sation of the taper if pain reappears. clinical response in a patient to the use of

486 DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005 Hays and Associates these adjuvants and the pain intensity the level of comfort prescribing this unique Crul B: Methadone for phantom limb patient is experiencing is moderate to se- drug to their patients. pain. Clin J Pain 18:203–205, 2002 vere, we will quickly turn to methadone as 7. Fishman S, Wilsey B, Mahajan G, Molina our opioid of choice. In our experience, P: Methadone reincarnated: novel clinical concerns regarding methadone’s significant References applications with related concerns. Pain interindividual variability in potency and 1. Fast Facts Concept #75: methadone for Med 3:339–348, 2002 the treatment of pain [article online], 8. Bruera E, Sweeney C: Methadone use in long and variable half-life have been mini- patients with pain: a review. J Pal- mally problematic with proper dosage initi- 2002. Available from http://www.eperc. mcw.edu/fastFact/ff_75.htm. Accessed liat Med 5:127–138, 2002 ation and subsequent appropriate dose 9. Mercadante S, Casuccio A, Agnello A, Ser- titration. The treatment of persistent pain, 18 October 2004 2. Foley K: Opioids and chronic neuro- retta R, Calderone L, Barresi L: Morphine in general, and specifically the treatment of pathic pain (Editorial). N Engl J Med 384: versus methadone in the pain treatment of painful diabetic peripheral neuropathy, 1279–1281, 2003 advanced cancer patients followed up at should not be left to be treated exclusively 3. Gagnon B, Almahrezi A, Schreier G: Meth- home. J Clin Oncol 16:3656–3661, 1998 by pain specialists. There are too many pa- adone in the treatment of neuropathic pain. 10. Davis M, Walsh D: Methadone for relief of tients living with persistent pain and too few Pain Res Manag 8:149–154, 2003 : a review of pharmokinetics, noninvasive pain specialists to deal with all 4. Morley J, Bridson J, Nash T, Miles J, White pharmacodynamics, drug interactions of these patients. Referrrals to pain special- S, Makin M: Low-dose methadone has an and protocols of administration. Support ists for painful diabetic peripheral neurop- analgesic effect in neuropathic pain: a dou- Care Cancer 9:73–83, 2001 11. Pasero C, Portenoy K, McCaffery M: Opioid athy should be primarily limited to those ble-blind randomized controlled crossover analgesics. In Pain Clinical Manual. 2nd ed. cases that have remained refractory to the trial. Palliat Med 17:576–587, 2003 5. Attal N, Guirimand F, Brasseur L, Gaude B. Bowlus, Ed. St. Louis, MO, Mosby, 1999, reasonable therapeutic interventions of V, Chauvin M, Bouhassira D: Effects of IV p. 185–186 their primary care physicians or endocrinol- morphine in central pain: a randomized 12. Gouldin WM, Kennedy DT, Small RE: ogists. Many practitioners, with appropriate placebo-controlled study. 58: Methadone: History and Recommendations education and some practice using metha- 554–563, 2002 for Use in Analgesia. APS Bulletin. Glen- done, will find that they will reach a real 6. Bergmans L, Snijdelaar D, Dirk G, Katz J, view, IL, American Pain Society, 2002

DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005 487