Practical guide for using methadone in pain and palliative care practice
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/IJPC.IJPC_186_17
Source of Support: None, Conflict of Interest: None
Since the 2014 Amendment to the NDPS Act methadone has been released in India for pain management. The methadone is supplied as racemic mixture with R & S methadone with benefit in pain management and associated adverse effects. Physicians need to be aware of adverse effects so that methadone can be administered safely. Similarly, patients and families need to store and use methadone carefully and experience the benefits and not increase the risk of further morbidity. Considerable amount of literature on methadone is available and sometimes conflicting, hence the article is attempting to guide a physician to use methadone safely to acquire experience and expertise over time.
Keywords: Drug interaction, equianalgesic dose, methadone, neuropathic pain, opioid rotation
Methadone is a synthetic opioid and classified as WHO Ladder Step 3, strong opioids such as morphine and fentanyl. Methadone was introduced as an analgesic in the mid-1940s but soon lost favor because of its side effect profile. A better understanding of pharmacokinetics and dynamics resulted in reemergence of methadone in the 1980s. Oral methadone as an analgesic was included in the 20th edition, WHO model list of essential medicines in 2017.
In India, methadone was introduced as a substitution therapy medication for opioid dependence treatment in the year 2012. It became commercially available for pain management in 2014. In 2015, the Government of India listed methadone as an “Essential Narcotic Drug” for medical and scientific use under the modified NDPS Act 2015.
R-Methadone is a Mu & Delta agonist, while S-Methadone is an NMDA antagonist, Serotonin and Norepinephrin re-uptake inhibitor. Methadone as racemic mixture has unique properties as a pharmaceutical, to improve complex chronic noncancer or cancer pain with nociceptive and neuropathic components.,
Some basic pharmacokinetic and pharmacodynamic properties of methadone, which may have a significant bearing on clinical practice [Table 1]:
According to the WHO analgesic ladder, pain may be classified as mild, moderate, or severe. The step of the ladder and the analgesic is chosen according to severity of pain [Figure 1].
When pain cannot be controlled with an opioid despite adequate dose titration, or when adverse effects become intolerable, [Table 2], the opioid can be switched to another opioid, a practice called opioid rotation or switch.
Methadone is commonly used as a replacement (substitution or conversion) medication when patients develop opioid toxicity, opioid tolerance, allergic, or are unable to tolerate the side effects of morphine or other strong opioids [Table 2].,
Special consideration in Indian context
Methadone is very useful for managing complex chronic pain syndromes (combination of nociceptive and neuropathic), which are commonly seen in the top three cancers in India, namely, cervical, head and neck, and breast cancers. The typical examples are cervical cancer with lumbosacral plexopathy and progressive oral cancer with compression on the branches of trigeminal nerve. Methadone can play a significant role if long-acting medication is needed or if the availability of morphine or cost become an issue.
S-Methadone has unique adverse effects like QT/ QTCprolongation and Serotonin syndrome. R-Methadone, a Mu agonist, exhibits similar adverse effects as other opioids, but nausea, constipation, and confusion are less common than other opioids [Table 3].
How to recognize opioid-induced neurotoxicity
Opioidinduced neurotoxicity (OIN) causes symptoms such as hyperalgesia (exaggerated sensitivity to the existing pain), allodynia (normally nonnoxious stimuli resulting in a painful sensation), delirium with hallucinations, and sometimes myoclonus, leading to seizures.,, OIN results from the accumulation of toxic metabolites of opioids, for example, morphine-3-glucuronide in the case of use of morphine. OIN can be precipitated by factors such as impaired renal function, dehydration, electrolyte imbalances, and high-dose parenteral administration of morphine. The management of OIN is to consider hydration and if needed, opioid rotation.
Methadone should not be used in conditions such as patients who are hypersensitive to the active substance, severe liver  and respiratory failure, pain conditions such as mild, intermittent, or short duration pain that can be managed with other analgesics and in acute unstable pain, patients taking monoamine oxidase inhibitors (or within 14 days of such therapy) [Table 4].
Use caution when using methadone in the following:
There are no conclusive prospective and comparative studies available to recommend one single best dosing strategy. Based on limited research evidence and clinical experience, the practical advice is to initiate methadone at low doses, individualize the treatment based on indication and prior opioid exposure status, titrate slow, and monitor patients for adverse effects such as sedation. Before starting methadone, complete an individualized medical and behavioral risk/benefit evaluation.
Initiating methadone in opioid-naïve patients
Initiating methadone as a firstline opioid in an opioid-naïve patient is not a common practice. It is strongly recommended to consult with a pain and palliative care consultant in such situations.,
Initiating methadone on patients already on opioids
The conversion of other opioids when on higher doses to methadone should be performed carefully., Consider consultation with an experienced colleague until you have done many of these conversions. In all cases, have a colleague make the calculation as a cross-check?
Note: Methadone dose conversion is not a linear process.. [Table 5]. For example, 60 mg MEDD would have a conversion ratio 4:1 (15 mg of methadone/day) and 180 mg MEDD would have a conversion ratio of 8:1 (22.5 mg methadone/day).
Calculate methadone total daily dose equivalent (Step 1, 2, 3)
Once patients are on a stable methadone dose, the dose should be adjusted by increments of 10%–20% every 5–7 days and not earlier. For elderly patients or patients with impaired liver function, this adjustment period should be increased.
Adequate treatment of breakthrough pain during the conversion and dose-titration period using agents such as nonsteroidal anti-inflammatory drug or acetaminophen or a short-acting opioid such as morphine should be considered. Nonpharmacological interventions (radiation therapy, occupational therapy, consulting, or physiotherapy consultation to explore less painful ways of movement) can reduce the need for opioid breakthrough medications.
Methadone as a breakthrough medication is not advised for both baseline therapy and incident pain because of the potential for accumulation and inadvertent methadone overdose. However, when other opioids are contraindicated, methadone is rarely used as a breakthrough medication. It is important to remember that when methadone is considered for breakthrough pain, the patient and family should be adequately trained, specially, if they are otherwise used to morphine.
Calculation of dose of breakthrough methadone
Calculate p.r.n doses as a 10% of the total daily dose. There should be no more than three breakthrough doses per day to avoid accumulation.
Example: Patient is on methadone 5 mg PO q8H (15 mg/day), 10% is 1.5 mg. The breakthrough dose would be 1.5 mg q4 h prn, maximum 3 doses per day.
Monitor for sedation, lethargy, confusion, and respiratory depression every 6 h for 3–6 days after initiation or dose change and daily monitoring until at least day 10. Respiratory depression risk is reported greatest from day 4 to day 6.
Points to remember
The variable half-life of methadone means that some patients may not reach steady state (5 half-lives) for over 3 weeks.
Always, an effective breakthrough dose must be available.
Resist the temptation to reduce the breakthrough dose in parallel with reductions in the original opioid. Even though the original opioid is being reduced, methadone is being added, and the breakthrough dose must reflect the total opioids (i.e. the initially calculated morphine daily dose).
During the titration phase, close outpatient follow-up, daily telephone progress reports by the patient, family members, home health nurses, or hospice personnel are recommended. Patients should be informed that several titrations might be necessary to reach optimal pain control.
Outpatient initiation of methadone and rotation for cancer pain is safe and exhibits high success rates.
It is recommended that clinicians review patient medications before initiation of methadone and consider discontinuation or dose reduction of medications with potential interactions or additive side effects. Drugs that can increase risk and require attention as below:
Methadone in moderate-to-high doses can prolong the QTc interval and may induce torsades de pointes (TdP). A QTc interval of >450 ms is associated with increased risk. It is recommended not to use methadone in patients with a baseline QTc interval >500 ms.,
Risk factors for QT/QTc prolongation when on methadone
Guidance for QTc interval screening
In patients without new risk factors for QT/QTc interval prolongation, an electrocardiogram (ECG) within the previous 3 months with a QTc <450 ms can serve as the baseline study.,
Consider baseline ECGs when
Monitoring and followup ECGs when
If the QTc interval is found to be ≥500 ms
If the QTc interval is found to be ≥450 ms but <500 ms
Electrocardiograms monitoring when using methadone in advanced illness situation
In advanced illness and end-of-life-care situations, when the goal of care is comfort care, there should be informed discussion with the patient and the family members about the potential risk for cardiac arrhythmia, and it is recommended to initiate/continue with methadone treatment without subjecting the patient to unnecessary investigations which may affect the quality of life.
Methadone toxicity may manifest many hours or days after a dose change. Main protection against overdose is vigilance and education. Methadone overdose occurs under the following circumstances:
Suspect methadone overdose when patient exhibits excess somnolence, pinpoint pupils, respiratory rate <8/min, systolic blood pressure <90 mmHg, or 20% less than baseline.
Methadone overdose is reversed with naloxone.
Mix one ampule (0.4 mg) of naloxone in 9 ml of sterile normal saline (0.04 mg naloxone/ml). Administer 1 ml of diluted naloxone every 2–4 min until patient recovers from clinical signs of overdose. Once a conscious level is achieved, repeated naloxone dosing (or an infusion titrated to effect) may be required for some time due to the slow clearance of methadone.
Care should be taken to administer minimum safe dose. Complete reversal of methadone may precipitate pain crisis.
Switching methadone to alternative safe opioids may be required in the event of unacceptable side effects or unresolved pain. The equivalent dose ratio when switching from methadone to another opioid is not a reverse process. There is no acceptable standard conversion strategy for switching from methadone to another opioid. A proposed safe and conservative approach is a 1:3 methadone to morphine ratio (10 mg methadone/day = 30 mg oral morphine/day).,,
Methadone is available as liquids and tablets. The liquid contains 150 ml and contains 1 mg/ml. The tablet is available as 5 mg strength. It can be administered orally, sublingually, or buccally.
Before prescribing methadone, educate and counsel patients about the indications for treatment, goals of therapy, and possible adverse events – either face to face or by phone. There should be a commitment from the patient and the family about the need for adherence to treatment, monitoring, reporting, and follow-up. It is important that the patient or family learn accurate dose measurement using a syringe (for liquid methadone) or the tablet. They should shake bottle of liquid before use and use same, accurate measuring device for liquid methadone. Patients should be instructed to call the prescribing physician if there is a change in status such as the need to use >4 or 5 breakthrough opioid doses/day.
The patient information sheet should carry the following instruction:
Patients at home should be instructed to take following precautions:
Methadone is an effective analgesic for the management of chronic complex pain such as chronic neuropathic pain syndromes seen in cancer when not responding to other strong opioid medications such as morphine or fentanyl. The distinct pharmacokinetic and pharmacodynamic properties of methadone require caution when a patient is initiated, titrated, and maintained on methadone. The equianalgesic dose of methadone shows variability. Use MEDD to methadone conversion ratios or nomogram before titration. Methadone interacts with many medications, resulting in serious adverse reactions and be cautious. There have been reports of sudden deaths with the use of methadone due to its QT prolongation and TdP properties, particularly in higher dosage. Health-care professionals prescribing methadone should undergo special training in its usage and should strictly adhere to recommendations to avoid serious adverse events.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]