TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN (Tramadol Hydrochloride and Acetaminophen)

Australia TGA / PBS / State Schemes

Classified as S4 under the Therapeutic Goods Administration (TGA).

Flagged as reportable under SIRA guidelines in NSW. Claims involving this medication may require additional reporting and clinical justification.

SIRA best practice guidelines recommend a maximum opioid duration of 5 days for acute pain. Prescribing beyond this requires documented clinical justification and may trigger a Reasonable and Necessary determination.

WorkSafe Victoria Drugs of Dependence Guidelines require monitoring for all S8 opioids. WorkCover QLD Pain Intervention Guidelines recommend multimodal pain management with opioids as a last resort.

United Kingdom NICE / MHRA / FPM

NICE NG193 (Chronic Pain) recommends against initiating opioids for chronic primary pain. The Faculty of Pain Medicine (FPM) Opioids Aware resource recommends structured opioid prescribing with regular review, dose limits, and documented tapering plans.

For personal injury claims in the UK, opioid prescribing duration and dose should be reviewed against NICE and FPM guidelines. Costs may be recoverable as a disbursement in high-value PI claims.

UK drug driving laws (Section 5A Road Traffic Act 2006) set specific limits for prescription drugs that cause impairment. Employers and occupational health advisors should assess fitness to work.

United States FDA / CDC / State WC

FDA approved for use in the United States.

FDA Boxed Warning: WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF TRAMADOL HYDROCHLORIDE and ACETAMINOPHEN Addiction, Abuse, and Misuse Because the use of tramadol hydrochloride and acetaminophen exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) ]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of tramadol hydrochloride and acetaminophen, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride and acetaminophen are essential [see Warnings and Precautions (5.2) ]. Accidental Ingestion Accidental ingestion of even one dose of tramadol hydrochloride and acetaminophen, especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions (5.2) ]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of tramadol hydrochloride and acetaminophen and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3) , Drug Interactions (7) ]. NeonatalOpioidWithdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4) ]. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5) ]. Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases occurred following tonsillectomy and/or adenoidectomy, and in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [see Warnings and Precautions (5.6)] . Tramadol hydrochloride and acetaminophen is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4) ] . Avoid the use of tramadol hydrochloride and acetaminophen in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol [see Warnings and Precautions (5.6) ] . Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride and acetaminophen requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see Warnings and Precautions (5.7) , Drug Interactions (7) ] . Hepatotoxicity Tramadol hydrochloride and acetaminophen tablets contain tramadol hydrochloride and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product [see Warnings and Precautions (5.9) ]. WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF TRAMADOL HYDROCHLORIDE and ACETAMINOPHEN See full prescribing information for complete boxed warning. Tramadol hydrochloride and acetaminophen exposes users to the risks of addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing tramadol hydrochloride and acetaminophen, and monitor regularly for these behaviors or conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially during initiation or following a dose increase. ( 5.2 ) Accidental ingestion of tramadol hydrochloride and acetaminophen, especially by children, can result in a fatal overdose of tramadol. ( 5.2 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.3 , 7 ) Prolonged use of tramadol hydrochloride and acetaminophen, during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.4 ) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. ( 5.5 ) Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism ( 5.6 ). Tramadol hydrochloride and acetaminophen is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy ( 4 ). Avoid the use of tramadol hydrochloride and acetaminophen in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol. ( 5.6 ) The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride and acetaminophen requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1. ( 5.7 , 7 ) Tramadol hydrochloride and acetaminophen tablets contain acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen containing product. ( 5.9 )

The CDC Clinical Practice Guideline for Prescribing Opioids (2022) recommends non-opioid therapies as first-line treatment for pain. When opioids are prescribed, the lowest effective dose should be used for the shortest duration needed.

For workers compensation claims, many states require prior authorization for opioids beyond initial acute prescribing. State drug formularies (e.g. California MTUS, Texas, New York) may restrict or require step therapy before opioid approval.

New Zealand ACC / BPAC NZ / Medsafe

BPAC NZ recommends reassessing opioid therapy at regular intervals and limiting duration. The NZ Opioid Prescribing B-QuiCK Guide provides structured prescribing and tapering protocols.

ACC (Accident Compensation Corporation) covers treatment-related medications for accepted claims. Opioid prescribing beyond guidelines may require ACC clinical review and approval.