Methadone is in a class of medications called opiate analgesics. Methadone works to treat pain by changing the way the brain and nervous system respond to pain. Methadone can work as a substitute for opiates by producing effects similar to those that opiates produce. Methadone prevents withdrawal symptoms in people who have them as the result of discontinuing opiate use. Methadone comes as a tablet, a dispersible tablet (can be dissolved in liquid), a solution (liquid), and a concentrated solution (a liquid that must be diluted before use) to take by mouth.
Recommended for Practice
Miaskowski, C., Cleary, J., Burney, R., Coyne, P., Foster, R., Grossman, S., . . . Zahrbock, C. (2005). Guideline for the management of cancer pain in adults and children. APS Clinical Practice Guidelines Series. Glenview, IL: American Pain Society.
Type of Resource/Evidence-Based Process:
PROCESS OF DEVELOPMENT: An interdisciplinary panel of experts in cancer pain management prepared these guidelines. When unavailable, recommendations were not made or were made on the recommendation of experts in that area.
Results Provided in the Reference:
Guidelines & Recommendations:
- Make patient and family caregiver education about pain management a part of the treatment plan, and encourage patient and family caregivers to participate actively in pain management.
- Collaborate with patients and family caregivers, taking costs and availability of treatment options into account when selecting pain management strategies. (Panel consensus)
- Perform a comprehensive pain assessment of all patients with cancer at each outpatient visit or hospital admission and use each patient’s self-report as the foundation for the assessment.
- Include in the comprehensive pain assessment a detailed history to determine the presence of persistent and breakthrough pain and its effects on function; a psychosocial assessment; a physical examination; and a diagnostic evaluation of signs and symptoms associated with common cancer pain presentations and syndromes.
- Develop a systematic approach to cancer pain management and teach patients and family caregivers how to use effective strategies to achieve optimal pain control.
- Begin a bowel regimen to prevent constipation when the patient is started on an opioid analgesic.
- Administer a long-acting opioid on an around-the-clock basis, along with an immediate-release opioid to be used on an as-needed basis, for breakthrough pain once the patient’s pain intensity and dose are stabilized.
- Do not use meperidine in the management of chronic cancer pain.
- Adjust opioid doses for each patient to achieve pain relief with an acceptable level of side effects.
- Avoid intramuscular administration because it is painful and absorption is unreliable.
- Use optimally titrated doses of opioids and maximal safe and tolerable doses of coanalgesics through other routes of administration before considering spinal analgesics. (Panel consensus)
- Monitor for and prophylactically treat opioid-induced side effects.
- Clarify myths and misconceptions about pain management, and reassure patients and family caregivers that cancer pain can be relieved and that addiction and tolerance are not problems associated with effective cancer pain management.
- Use cognitive and behavioral strategies as part of a multimodal approach to cancer pain management, not as a replacement for analgesic medications.
- Offer patients who decline to have procedural sedation nonpharmacologic alternatives to decrease procedure-related pain.
- Implement a formal process to evaluate and improve the quality of cancer pain management across all stages of the disease process and across all practice settings.
- Evaluate the quality of cancer pain management at points of transition in the provision of services (e.g., from the hospital to the home) to ensure that optimal pain management is achieved and maintained.
Research Evidence Summaries
Anghelescu, D.L., Faughnan, L.G., Hankins, G.M., Ward, D.A., & Oakes, L.L. (2010). Methadone use in children and young adults at a cancer center: A retrospective study. Journal of Opioid Management, 7, 353–361.
To augment the literature on methadone applications in pediatric oncology
Intervention Characteristics/Basic Study Process:
This was a retrospective review of all patients treated with methadone at St. Jude Children’s Research Hospital over a five-year period (October 2001–September 2006).
- N = 41
- AGE = 7 patients were younger than 10 years old, 16 patients were aged from 11–17 years, and 18 patients were aged 18 years or older.
- MALES: 58.5%, FEMALES: 41.5%
- KEY DISEASE CHARACTERISTICS: Leukemia/lymphoma (31.2%), solid tumor (56.1%), hematologic/congenital disorders (9.8%)
- SITE: Single setting
- SETTING TYPE: Three inpatient units, multiple outpatient units
- LOCATION: Tertiary cancer center
Phase of Care and Clinical Applications:
- PHASE OF CARE: End-of-life care
- APPLICATIONS: Palliative care
- Retrospective review of demographic characteristics, diagnoses, type of pain (i.e., nociceptive, neuropathic, mixed), causes of pain, and indications, dose regimens, adverse effects, and outcomes of methadone treatment
- Inpatients and outpatients who received methadone during the study period were identified by reviewing the institution’s pharmacy records. Data were abstracted from the medical records. Data included age, sex, primary oncology diagnosis, type of pain experienced (i.e., nociceptive, neuropathic, or mixed) at the time of methadone prescription, and the clinical context of pain (i.e., chemotherapy, bone marrow transplant, amputation, limb-sparing surgery, tumor, other).
- The clinical uses of methadone also were ascertained from the medical records and were categorized as nociceptive pain unresponsive to other opioids (33.3%), neuropathic pain (39.2%), facilitation of opioid weaning and prevention of withdrawal (21.6%), and pain management at the end of life (5.9%).
- Pain intensity scores were recorded at the beginning of treatment with methadone, at weekly intervals during the first month, and at monthly intervals thereafter for the duration of treatment or six months.
- Adverse effects of methadone were captured by review of the outpatient clinic notes or the inpatient nursing or physician notes. Sedation, nausea, constipation, confusion, respiratory depression, and pruritus were recorded as present or absent.
- A successful outcome was defined as a reduction of pain scores between the start and end of methadone treatment and/or documentation of the effectiveness of treatment for the specified indication.
- Age-appropriate pain assessment tools were used as per the institution’s pain standard of care—the Face, Legs, Activity, Cry, Consolability (FLACC) scale for children younger than 3 years, the Wong-Baker FACES Pain Rating Scale for children aged 4–6 years, and the numeric rating scale for children aged 7 years or older.
Methadone dosing data were available for 37 patients. Four patient records lacked baseline doses because methadone was initiated at another institution. Starting doses ranged from 0.06–3.8 mg/kg/d. The highest methadone dose was 9.4mg/kg/d. More than one-third of the patients (34.1%) had no documented adverse effects. The most common adverse effect was sedation (24.4%). No respiratory depression or pruritus were documented. Pain reduction was reported by comparing the maximum pain score on the day that methadone was discontinued to the maximum pain score on the day that methadone was initiated. Fourteen of the 41 patients had documented pain scores for both time points. Nine patients (64.3%) showed reduction of the pain score, and seven (50%) had complete resolution of pain.
Methadone was effective for pediatric patients with neuropathic pain or nociceptive pain unresponsive to other opioids, and it effectively prevented opioid withdrawal.
- Small sample size
- Retrospective design
Prospective studies are needed to evaluate specific methadone regimens for each of the clinical entities described and to determine opioid conversion scales to and from methadone in the pediatric population.
Auret, K., Roger Goucke, C., Ilett, K.F., Page-Sharp, M., Boyd, F., & Oh, T.E. (2006). Pharmacokinetics and pharmacodynamics of methadone enantiomers in hospice patients with cancer pain. Therapeutic Drug Monitoring, 28, 359–366.doi: 10.1097/01.ftd.0000211827.03726.e4
To elucidate the pharmacology of methadone in palliative care patients with advanced cancer who have switched from morphine to methadone
- The sample was composed of 13 patients. Three patients did not complete the entire protocol.
- The sample consisted of patients with cancer pain that was poorly controlled with morphine or for whom morphine caused unacceptable side effects.
- Inpatient and outpatient palliative care services
- Perth, Western Australia
- Relationship between original serum morphine concentrations and final R- and S-methadone
- Degree of control of cancer pain and side effects
- Six patients achieved optimal pain control, but authors observed no obvious relationship between pain control and the plasma concentrations of either enantiomer.
- Of all patients, 46% of those who changed from morphine to methadone experienced an improvement in pain control.
The study had a small sample size.
Further studies, to determine if methadone is better than morphine for the treatment of neuropathic pain, are warranted.
Centeno, C., & Vara, F. (2005). Intermittent subcutaneous methadone administration in the management of cancer pain. Journal of Pain and Palliative Care Pharmacotherapy, 19(2), 7–12.doi: dx.doi.org/10.1080/J354v19n02_03
To study the dose, level of pain, and toxicity symptoms associated with intermittent subcutaneous methadone injections used to treat cancer pain
Intervention Characteristics/Basic Study Process:
Over seven days, patients whose pain was well controlled with oral methadone received subcutaneous methadone via a butterfly needle that was used exclusively for methadone. The conversion ratio, oral methadone to subcutaneous methadone, was 1:1.
- The sample was composed of 10 patients.
- The age range of patients was 46–81 years.
- The sample consisted of two females and eight males.
- All patients had advanced cancer (the study comprised multiple diagnoses), were hospitalized in a palliative care unit, and had achieved pain control (a pain rating of less than 5 on a 0–10 scale) on stable methadone doses.
- Single site
- Palliative care unit, Spain
- Numeric Rating Scale (NRS), 0–10, to measure the local discomfort of each injection
- Methadone dose used
- Toxicity symptoms
Two of 10 patients withdrew because of nonpainful irritation at the injection site. Compared to the methadone doses other patients were taking, these two patients took significantly higher doses: 40–45 mg, either every 8 hours or every 12 hours. All other patients’ doses were 5–25 mg, either every 8 hours or every 12 hours. Eight patients completed the study over seven days. Pain levels went from 3.3 to 3.5 on a 0–10 scale.
Intermittent subcutaneous methadone administration seems to be a useful alternative when oral administration is not feasible.
The study had a small sample size.
The conversion ratio, oral to subcutaneous methadone, was 1:1. This is not the currently recommended conversion ratio, though patients in the study experienced no increase in toxicity as the result of the 1:1 conversion. However, the duration of the study was only seven days; a longer duration may have resulted in toxicity effects. Higher doses caused local irritation. At even higher doses, clinicians may have to consider other strategies, such as adding dexamethasone to the infusion. If a patient is unable to take oral methadone, alternatives other than subcutaneous methadone—transdermal or buccal administration—are available.
Moryl, N., Kogan, M., Comfort, C., & Obbens, E. (2005). Methadone in the treatment of pain and terminal delirium in advanced cancer patients. Palliative and Supportive Care, 3, 311–317.doi: 10.1017/S1478951505050479
To document the use of methadone as part of an opioid-rotation strategy for the treatment of uncontrolled pain in patients with delirium at the end of life
Intervention Characteristics/Basic Study Process:
Ten patients rotated from morphine, five from fentanyl, two from hydromorphone, and three from fentanyl-morphine or morphine- hydromorphone combinations. Authors were purposefully conservative in calculating the starting methadone dose. Within the first week four patients expired, one changed to IV methadone, and two rotated back to morphine because of worsening delirium and inadequate analgesia. At two weeks, 10 patients had expired. Of the remaining 10, seven stayed on methadone. The average dose was 1.1 mg/hour. Two patients returned to morphine, and one was rotated to Percocet.
- The sample was composed of 20 patients with cancer who were experiencing severe pain and delirium at the end of life and whose delirium did not resolve 24 hours after administration of a neuroleptic.
- The age range of patients was 47–77 years.
- Ten males and 10 females participated in the study.
- The study included patients with a variety of cancer diagnoses.
Nonrandomized open-label prospective study
- Numeric analog scale (NAS), to measure pain
- Scale, 0–3, to measure sedation
- Memorial Delirium Assessment Scale (MDAS)
- Opioid dose
Pain control was significant in 15 of 20 patients; average analgesia was good to excellent. Sedation rating decreased from 1.65 to 0.55 on 1–3 scale. Cognitive status improved for nine patients. Six patients achieved moderate improvement in cognitive status; two, partial improvement; and three, no improvement. Three days after the switch from an opiod, average MDAS score improved from 23.6 to 10.6. Decreased alertness on methadone was devoid of agitation.
Methadone can be an acceptable alternative to an opioid in the treatment of refractory pain and terminal delirium. The use of methadone can minimize the need for sedation to treat delirium.
- The study had a small sample. Sample size decreased as patients expired.
- Authors did not specify the process of converting from an opioid to methadone.
- Many patients must be rotated to a different drug.
Nicholson, A.B. (2006). Methadone for cancer pain [Cochrane review]. In The Cochrane Library, Volume 4, 2006. Oxford, UK: Update Software.
To determine the effectiveness and safety of methadone analgesia in patients with cancer pain; to assess the adverse effects associated with methadone analgesia for the treatment of cancer pain
Databases searched were Cochrane Pain, Palliative & Supportive Care Group Trials Register; The Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; CancerLIT; CINAHL; National Research Register; CenterWatch clinical trials listing service; Current Controlled Trials; National Institutes of Health Clinical Trials Databases; BioMed; Glaxo Wellcome Clinical Trials Register; National electronic Library for Health (NeLH); System for Information on Grey Literature in Europe (SIGLE); Dissertation Abstracts OnDisc; Index to Theses (ASLIB Index); Proquest Digital Dissertations; Cochrane Database of Systematic Reviews (CDSR); and Database of Abstracts of Reviews of Effects (DARE).
Studies were included if they
- Involved patients of any age and gender with cancer pain that was chronic and of any intensity and any pain with a malignant etiology. (Etiology could be primary or secondary malignancy, solid or hematologic).
- Involved patients in a home, outpatient, or inpatient setting.
- Studies were excluded if they involved patients who took methadone for the suppression of cough or patients taking or who had taken methadone for rehabilitation from opioid dependence.
- Of studies retrieved, author analyzed only randomized, controlled trials that assessed symptom control of cancer pain. The control group could be a placebo or an active control. Active controls included any opioid other than methadone, another analgesic, or an adjuvant analgesic. Author accepted published and unpublished trials and, in determining eligibility, established no size restriction.
Six of the analyzed studies used only the oral route.
- Three studies compared methadone to morphine.
- One study compared methadone to a methadone-ibuprofen combination.
- One study compared methadone to dextromoramide or pethidine.
- One study compared methadone to diamorphine with cocaine.
Two of the analyzed studies compared oral and parenteral routes of administration.
- One study compared IM morphine with IM methadone with oral methadone
- One study compared methadone with morphine administered intravenously and orally.
- The final study the author analyzed compared methadone with morphine analgesia delivered by a patient-controlled IV infusion system.
- Starting doses, titration schedules, and pain scoring varied widely among analyzed studies.
- The sample included patients, of any age and gender, with cancer pain that was chronic and with a malignant etiology. (Etiology could be a primary or secondary malignancy, solid or hematologic). The pain could be of any intensity. Patients could have been at home or in an outpatient or inpatient setting.
- Patients were excluded from the study if they were taking methadone for suppression of cough or if they were taking or had taken methadone for rehabilitation from opioid dependence.
- Of the trials retrieved, the author analyzed nine randomized controlled trials (six double-blinded trials and two crossovers).
- The sample was composed of 459 recruits, of whom 392 completed the trials.
- All studies involved an active placebo (five morphine, one dextromoramide or pethidine, one diamorphine-cocaine mixture). In each study the starting dose was different, as was each titration regimen and each pain scale.
- Six trials were inpatient studies. Two were outpatient studies. Author added one outpatient study after the last review, to make a total of three outpatient studies analyzed.
Evidence suggests that methadone is an analgesic with an efficacy similar to that of morphine and with side effects that are similar to those of morphine. Although methadone is similar to morphine, the pharmacokinetics and pharmacodynamics of methadone make dose titration difficult. Methadone presents the risk of drug accumulation to toxic levels. There is a significant danger that the effect of methadone accumulation leading to delayed onset of adverse effects has not been represented. The majority of studies involved were single-dose comparisons or pertained to short-term use. Such comparisons fail to reproduce clinical practice; such studies do not reveal delayed adverse effects. One study, which compared methadone to morphine over 28 days, reported an increased rate of withdrawal from the methadone group. Withdrawal was due to side effects. Author drew no conclusion regarding the relative merits, in the management of various pain syndromes, of methadone compared to those of other opioids. The additional study found methadone to be as effective as morphine in the treatment of neuropathic pain, but not superior to morphine.
Few studies presented complete data sets regarding pain. No meta-analysis was possible.
Quigley, C. (2008). Opioids in people with cancer-related pain. Clinical Evidence, 2008, 2408.
To determine the effects of various opioids in treating cancer-related pain
- Databases searched were MEDLINE, EMBASE, the Cochrane Library, National Health Service Centre for Reviews and Dissemination, Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Clinical Excellence (NICE).
- Authors did not include search keywords in the report.
Studies were included if they
- Were systematic reviews or randomized controlled trials whose results were published in any language.
- Included more than 20 participants, of whom investigators followed up with 50%.
- Authors did not list exclusion criteria.
Investigators reviewed 34 studies. Investigators used 22 studies as the basis of their report. Investigators evaluated studies by performing a GRADE evaluation of the evidence, using the following criteria: type of evidence, quality, consistency (similarity of results across studies), directness (generalizability), and effect size. Evidence ratings were very low, low, moderate, and high.
- Authors did not specify total sample size.
- The sample included patients with cancer-related pain.
Authors reported results relative to pain, need for rescue analgesia, function, quality of life, patient preference, and adverse events.
Morphine is the standard opioid in the management of moderate to severe cancer pain. Evidence from this study was insufficient to allow authors to compare other opioids to it. Evidence from this study was insufficient to allow conclusions about codeine. Investigators categorized the effectiveness of dihydrocodeine, a newer option for pain control, as unknown. Evidence from this study was insufficient to allow authors to rate the effectiveness of transdermal fentanyl. Hydromorphone may be as effective as morphine or oxycodone and may cause fewer adverse effects. Methadone may be as effective as morphine or oxycodone, for reducing pain, and the two opioids' rates of associated adverse effects are similar. Oxycodone and morphine may be equally effective in reducing pain. Tramadol may be as effective as morphine, but morphine seems to have quicker onset.
Authors deemed all evidence cited in this review to be of very low or low quality.
Wiffen, P.J., & McQuay, H.J. (2010). Oral morphine for cancer pain. Cochrane Database of Systematic Reviews 2010(8).doi: 10.1002/14651858.CD003868.pub2
To determine the efficacy of oral morphine in bringing relief from cancer pain; to assess the incidence and severity of side effects associated with oral opioids
- Databases searched were MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL); Cochrane Pain, Palliative and Supportive Care Group Trials Register; and Oxford Pain Relief Database. In addition, investigators performed manual searches of 40 key journals that list pain-related trials.
- Search keywords were analgesics, opioid (*administration and dosage), morphine, (*administration and dosage), neoplasms (*complications) pain (*drug therapy, radiotherapy), randomized controlled trials (RCT). Investigators searched for studies relating to humans, adults, and children.
Studies were included if they
- Were RCTs.
- Had been published as full journal articles.
- Compared an oral morphine preparation to placebo, active control, or alternative route of morphine.
- Included adults or children with cancer pain that required opioids for treatment.
- Studies were excluded if they were quasi-randomized studies, included 10 or fewer participants, did not assess pain as an outcome measure, focused on pain unrelated to cancer.
The search retrieved 133 studies; 62 met inclusion criteria. After elimination of duplicates, the group for analysis included 54 studies. There were insufficient data to perform meta-analysis. Study quality was evaluated using the Jadad scale. Overall, the quality of studies was high, with a median score of 4 on a five-point scale. Studies included comparisons of modified- and immediate-release opioids, comparisons of morphine versus other drugs, and comparisons of the effects of morphine delivered by different routes and delivery mechanisms.
The 54 studies involved a total sample of 3,749 participants. Sample range was 11–699.
- Fifteen studies compared modified-release morphine to immediate-release morphine. The trials showed that both forms were similar in terms of pain relief provided and adverse effects experienced.
- Twelve studies compared various doses or dose intervals of modified-release morphine. The trials revealed no significant differences across products in terms of pain intensity, rescue analgesia, or adverse effects.
Thirteen studies compared modified-release morphine with other opioids, including oxycodone, hydromorphone, transdermal fentanyl, dextropropoxyphene, tramadol, and methadone.
- Comparisons of modified-release morphine with oxycodone showed that both resulted in adequate analgesia. Studies revealed some differences in side-effect profiles.
- In a comparison of modified-release hydromorphone and modified-release morphine, both achieved satisfactory pain control. Authors noted no difference regarding the use of rescue medications.
- Comparisons of oral morphine and transdermal fentanyl showed no significant differences between treatments in regard to pain control. However, more patients receiving fentanyl required upward-dose titration and more rescue medication. Transdermal fentanyl was associated with less sedation and less constipation. Dose-equivalency determination appeared to be problematic in one trial.
- One small study found that, compared with morphine, dextropropoxyphene was associated with fewer side effects and lower doses needed for pain relief
- One study of tramadol versus morphine in opioid-naive patients revealed that both medications resulted in satisfactory analgesia but that tramadol was more effective in treating neuropathic pain.
- One study, which compared methadone to oral morphine, showed that a greater number of adverse events were associated with methadone than with oral morphine.
Six studies compared immediate-release morphine to other opioids, including Brompton cocktail, methadone, tramadol, oxycodone, and oral transmucosal fentanyl citrate.
- Comparisons of oral morphine to Brompton cocktail showed no difference between treatments and demonstrated that cocaine did not enhance analgesia.
- One comparison involving morphine and methadone showed that both drugs achieved pain control but that more patients on morphine complained of dry mouth and that more patients on methadone complained of headache.
- Tramadol and morphine use resulted in a pain decrease to similar intensities.
- One study, which compared morphine to immediate-release oxycodone, revealed that the two achieved similar control of pain. The most frequent side effect of both was sedation. Oral morphine was associated with more nausea than was oxycodone.
- In one study, patients could use either morphine capsules or oral transmucosal fentanyl (OTFC) for breakthrough pain. OTFC was more successful than morphine at reducing pain intensity, and the majority of patients preferred OTFC.
- The studies showed no significant difference in pain control or adverse events between oral and rectal administration or between tablets and oral suspension.
- Compared to naproxen, morphine was associated with greater use of rescue medication.
- The studies showed that oral morphine and epidural morphine produced a similar level of pain relief. The epidural route was associated with fewer side effects but more technical problems.
- Oral morphine and morphine suppositories provided a similar level of pain control. Studies showed no difference in the adverse effects associated with these two interventions.
- Various studies compared different medication routes or morphine to nonopioids. Across studies there was a 6% withdrawal rate due to adverse effects.
The literature demonstrates the effectiveness of morphine with titration to effect. The range of doses used in studies varied widely, with the maximum dose recorded being 2000 mg/day. Mean daily dose was 110–250 mg/day. This shows effectiveness over a wide range and that oral morphine, at the correct dose for the individual, is as effective as other opioids and morphine adminstered through nonoral routes. Limited evidence shows that transdermal fentanyl is faster than oral morphine at dealing with breakthrough pain. Some evidence shows that transmucosal fentanyl may be superior to oral morphine in the treatment of breakthrough pain and that fentanyl patches are associated with fewer side effects at the same level of analgesia. Oxycodone, hydromorphone, and morphine provide comparable pain control and are associated with similar adverse events. A small number of patients appear to develop intolerable side effects as the result of using oral opioids. Findings support the effectiveness of various forms of opioids for pain control, and the appropriateness of dose titration across a wide range, with specific medication selected according to each patient's responses and preferences.
These findings show that titrating to pain relief, using modified-release opioids, is possible.