Side Effects of Methadone Treatment
Methadone treatment causes common side effects including lightheadedness, dizziness, sedation, nausea, vomiting, and sweating during initial administration, with constipation and sweating often persisting during long-term maintenance, but these risks are substantially outweighed by the dramatic mortality reduction of approximately 25 fewer deaths per 1000 person-years compared to no treatment. 1, 2
Acute Side Effects During Initial Administration
The most frequently observed adverse reactions during methadone initiation include 1:
- Lightheadedness, dizziness, and sedation (particularly prominent in ambulatory patients not suffering severe pain) 1
- Nausea, vomiting, and sweating 1
- Constipation and dry mouth 1
Life-Threatening Risks Requiring Immediate Attention
Respiratory Depression
Respiratory depression is the chief hazard associated with methadone administration, particularly concerning in elderly or debilitated patients and those with conditions accompanied by hypoxia or hypercapnia 1. Methadone's peak respiratory depressant effects occur later and persist longer than its peak analgesic effects, contributing to cases of iatrogenic overdose particularly during treatment initiation and dose titration 1.
Cardiac Conduction Effects
Methadone inhibits cardiac potassium channels and prolongs the QT interval, with cases of torsades de pointes observed during treatment 1. These cases appear more commonly associated with higher dose treatment (>200 mg/day), though cases have been reported at doses commonly used in maintenance treatment 1. Administer methadone with particular caution to patients already at risk for prolonged QT interval (cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia) 1.
Critical Mortality Risk Periods
The first four weeks of methadone induction carry the highest mortality risk, though this decreases substantially during this period and stabilizes at approximately 6 deaths per 1000 person-years during continued treatment 2. The four weeks immediately after cessation of methadone treatment show extremely high mortality risk, potentially exceeding 30 deaths per 1000 person-years 2.
Chronic Side Effects During Maintenance
During prolonged administration in maintenance treatment programs, there is usually gradual, progressive disappearance of side effects over several weeks 1. However, constipation and sweating often persist throughout treatment 1.
Additional chronic effects include 1:
Opioid-Induced Hyperalgesia and Pain Intolerance
Patients receiving methadone maintenance develop a "syndrome of pain facilitation" with latent hyperalgesia secondary to long-term opioid exposure, demonstrating lower pain tolerance than opioid-naïve individuals 2, 3. This hyperalgesia involves neuroplastic changes with excitatory amino acid (N-methyl-D-aspartate) and opioid receptors, counteracting opioid analgesia and complicating acute pain management 2. Their pain experience is worsened by subtle withdrawal syndromes, intoxication, withdrawal-related sympathetic arousal, sleep disturbances, and affective changes 3, 4.
Withdrawal Symptoms During Induction Phase
During the induction phase, patients being withdrawn from heroin may exhibit typical withdrawal symptoms that should be differentiated from methadone-induced side effects 1:
- Lacrimation, rhinorrhea, sneezing, yawning 1
- Excessive perspiration, fever, chilliness alternating with flushing 1
- Restlessness, irritability, weakness, anxiety, depression 1
- Tremors, tachycardia, abdominal cramps, body aches 1
- Anorexia, nausea, vomiting, diarrhea, intestinal spasms 1
Drug Interactions and Contraindications
Patients receiving other CNS depressants (opioid analgesics, general anesthetics, phenothiazines, tranquilizers, sedatives, hypnotics, or alcohol) concomitantly with methadone may experience respiratory depression, hypotension, profound sedation, or coma 1.
Mixed agonist-antagonist opioids (pentazocine, nalbuphine, butorphanol) can precipitate acute withdrawal syndrome and should never be used 2, 4.
Less Common but Serious Adverse Reactions
Additional adverse reactions include 1:
- Agitation, confusion, seizures, disorientation 1
- Pulmonary edema 1
- Reversible thrombocytopenia (described in opioid addicts with chronic hepatitis) 1
- Hypokalemia, hypomagnesemia 1
- Visual disturbances 1
Critical Safety Context
Despite these side effects, all-cause mortality during methadone treatment is 11.3 per 1000 person-years compared to 36.1 per 1000 person-years out of treatment, representing approximately 25 fewer deaths per 1000 person-years for those retained in treatment 2. The potential risks of methadone should be weighed against the substantial morbidity and mortality associated with untreated opioid addiction 1.