What are the long-term risks of using tramadol (opioid analgesic)?

Long-Term Risks of Tramadol

Tramadol carries significant long-term risks including dependence, tolerance, withdrawal symptoms, persistent adverse effects (particularly gastrointestinal and CNS), respiratory depression, seizure risk, and serotonin syndrome, with evidence supporting efficacy only up to 3 months and no RCT data beyond 1 year. 1, 2

Evidence-Based Duration Limitations

The most critical long-term risk is prescribing beyond the evidence base:

• No randomized controlled trial evidence exists for tramadol use beyond 1 year, representing a fundamental knowledge gap about safety and efficacy in extended use 1, 2
• Clinical trials demonstrate only "very modest" beneficial effects for long-term (3 months to 1 year) management of non-cancer pain 1
• Systematic reviews show that less pain relief occurs during longer trials, suggesting diminishing returns and potential tolerance development with extended use 1, 2
• Most acute pain studies lasted fewer than 3 weeks, and chronic pain studies extended only to 3 months 2

Physical Dependence and Withdrawal

Long-term tramadol use creates substantial risk of physical dependence:

• Withdrawal symptoms occur if tramadol is discontinued abruptly, including anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations 3
• Less frequent but serious withdrawal symptoms include panic attacks, severe anxiety, and paresthesias 3
• Clinical experience suggests withdrawal can be avoided only by tapering at discontinuation 3
• While one 6-month study reported only 6% of patients experienced withdrawal symptoms, this still represents a clinically significant risk 4

Persistent Adverse Effects

Long-term tolerability data reveals ongoing side effect burden:

• Approximately 49% of patients report adverse events during extended use, with 66% of these directly related to tramadol treatment 4
• Gastrointestinal events (nausea and vomiting) remain the most frequent adverse effects even with sustained-release formulations 4
• CNS effects including dizziness, sedation, and impaired mental/physical abilities persist, affecting driving and machinery operation 3
• Serious adverse events occur in 6.4% of patients on long-term therapy 4

Respiratory Depression Risk

Though lower than traditional opioids, respiratory depression remains a concern:

• Tramadol causes respiratory depression, particularly when combined with CNS depressants including alcohol, other opioids, anesthetic agents, phenothiazines, tranquilizers, or sedative hypnotics 3
• Risk is markedly exaggerated in patients with increased intracranial pressure or head injury due to carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure 3
• Large doses combined with anesthetic medications or alcohol can result in clinically significant respiratory depression requiring overdose management 3

Seizure Risk

Tramadol uniquely lowers seizure threshold:

• Tramadol may reduce seizure threshold and is contraindicated in patients with seizure history 5, 3
• Risk increases with higher doses, particularly exceeding 400 mg/day 2
• Seizure risk is further elevated when combined with other seizure-threshold lowering drugs 6
• Naloxone administration for overdose may paradoxically precipitate seizures 3

Serotonin Syndrome

The monoaminergic mechanism creates unique interaction risks:

• Tramadol is contraindicated with MAO inhibitors and requires extreme caution with SSRIs, SNRIs, or tricyclic antidepressants due to potentially fatal serotonin syndrome 2, 3
• This risk persists throughout treatment duration and distinguishes tramadol from pure opioid agonists 3
• Concomitant use with these medications increases risk of both seizures and serotonin syndrome 3

Abuse and Diversion Potential

While lower than traditional opioids, misuse risk exists:

• Tramadol has mu-opioid agonist activity and can be sought by individuals with addiction disorders, subject to criminal diversion 3
• The FDA classifies tramadol as Schedule IV, acknowledging accepted medical use but recognized abuse potential 2
• Misuse or abuse poses significant overdose and death risk, particularly when combined with alcohol or other CNS depressants 3
• Deaths have occurred from accidental ingestion of excessive quantities alone or in combination with other drugs 3

Overdose Consequences

Long-term use increases cumulative overdose risk:

• Acute overdosage manifests as respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death 3
• Fatal overdose risk increases substantially when tramadol is abused concurrently with alcohol or other CNS depressants 3
• Naloxone reverses only some symptoms while increasing seizure risk 3
• Hemodialysis is ineffective, removing less than 7% of administered dose in 4 hours 3

Special Population Risks

Certain patients face amplified long-term risks:

• Patients over 75 years require dose reduction to 50 mg every 12 hours to minimize seizure risk 2
• Hepatic or renal impairment necessitates similar dose reduction due to drug accumulation risk 2, 5
• CYP2D6 polymorphism affects metabolism, leading to variable analgesic response and increased toxicity in some patients 2

Clinical Context and Positioning

The American College of Rheumatology provides critical framing:

• Tramadol is conditionally recommended only when patients have contraindications to NSAIDs, find other therapies ineffective, or have no available surgical options 1
• When an opioid is necessary, tramadol is conditionally preferred over non-tramadol opioids due to lower abuse potential 1, 7
• Use the lowest possible doses for the shortest possible length of time, given high risk of toxicity and dependence 1, 2
• The 85% incidence of adverse events in patients on opioids necessitates ongoing evaluation of whether benefits justify continued use 2

Critical Prescribing Pitfall

Do not assume long-term efficacy based on short-term response: evidence quality diminishes substantially beyond 3 months, and prescribing beyond 1 year represents practice outside the evidence base requiring exceptional clinical justification 2.