Tramadol

Tramadol in pain management

1. tramadol Dr. Darendrajit MD Senior Resident Department of PMR AIIMS, BBSR

2. FEW TERMS Opium: A dark brown, resinous material obtained from poppy ( Papaver somniferum ) capsule Opiate: Alkaloid compounds found in the opium 25 different alkaloids Morphine (10% in opium), Codeine (0.5% in opium) Thebaine (0.2% in opium ) Opioid: group of substance that have the analgesic and other properties of morphine Modern term Both natural and synthetic

3. Opioid receptors and their effects

4. TRAmadol Centrally-acting analgesic with a unique, dual mechanism of action 1. μ (mu-opioid) receptor agonist- 40% 2. W eak inhibitor of norepinephrine ( NE, 40% ) and serotonin reuptake (5-HT, 20% ) Considered to be a more potent analgesic than oral NSAIDs Have fewer gastrointestinal, renal , and cardiac side effects Reduced risk of abuse, physical dependence, sedation, and constipation

5. formulations Epidural IV/IM Rectal Oral route (immediate and sustained release)

6. MECHANISM OF ACTION/PHARMACODYNAMICS D ual mode of action: 1. B inds weakly to the μ-opioid receptor sites Affinity for the μ-opioid receptor is 1/6000 that of morphine and 1/10 that of codeine 2. Inhibits the reuptake of norepinephrine and serotonin Supported by the findings that analgesia is partially blocked by naloxone, α2-adrenoceptor antagonist ( yohimbine ), ondansetron

7. Pain pathway

8. MECHANISM OF ACTION/PHARMACODYNAMICS Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine Chemical name is cis-2-[( dimethylamino )methyl ]-1- (3-methoxyphenyl) cyclohexanol hydrochloride Parent compound is a racemic drug, and both its (+) and (−) forms play an important role in its mechanism The (+) enantiomer has a higher affinity for the μ-receptor and increases serotonin levels The (− ) enantiomer increases norepinephrine levels (1R,2R)- & (1S,2S)-Tramadol Enantiomers

9. MECHANISM OF ACTION/PHARMACODYNAMICS Extensively metabolized by the liver, with the major pathways being: N- and O- demethylation (phase 1) and glucuronidation or sulfation Eliminated primarily through the kidneys, with 30% being excreted unchanged .

10. MECHANISM OF ACTION/PHARMACODYNAMICS 23 identified metabolites, 11 are phase 1 and 12 are conjugates M1 metabolite shown to play a significant role in tramadol’s analgesic properties M1 metabolite is the O- demethylated form of tramadol with the (+) form having the greater potential for analgesic effect

11. MECHANISM OF ACTION/PHARMACODYNAMICS CYP2D6 ( isoenzyme of the cytochrome P450) responsible for conversion to the M1 metabolite Tramadol M1 metabolite 7 % of the population lacks this isoenzyme , therefore, tramadol metabolizes poorly and provides decreased analgesia Analgesic potency of the M1 metabolite is 6 times greater than that of its parent drug 200 × greater affinity to the μ-opioid binding site CYP2D6 O- demethylation

12. MECHANISM OF ACTION/PHARMACODYNAMICS Bioavailability after oral administration is 75%, with only 20% binding to plasma proteins

13. DOSAGE Average dose for a healthy adult is 50–100 mg every 6 h Peak plasma levels after a single 100-mg dose are 1.6 h for the parent drug and 3 h for the M1 metabolite Half-life levels after a single 100-mg dose are 6.3 h for the parent drug and 7.4 h for the M1 metabolite Analgesic benefit peaks at 2 h after the initial dose and lasts approximately 6 h, with steady state occurring after 48 h

14. DOSAGE When given with food, % absorbed and peak plasma conc. are unaffected, but the time to peak plasma conc. increases by 35 min Dosage adjustment is recommended in the elderly and in patients with renal and liver disease Dose recommended is 400 mg in a 24-h period secondary to the increased risk of side effects with higher doses

15. DOSAGE Ondansetron , a serotonin 5HT-3 receptor antagonist, inhibits the analgesic effects of tramadol Synergistic effect with other sedating medication, which may necessitate a dosage adjustment

16. SPECIAL POPULATIONS E lderly and/or patients with liver or renal disease require an adjustment in the usual dosage of tramadol Due to the increased elimination time of the drug in the elderly (75 years and older), the dosage should not exceed 300 mg/d Advanced liver disease prolongs the drug’s half-life and requires dosage reduction to 50 mg every 12 h (max daily dose 100 mg/d) Ultracet is not recommended for patients with liver disease

17. SPECIAL POPULATIONS Excretion: primarily through the kidneys Rate and extent of excretion will be significantly reduced in patients with a creatinine clearance of less than 30 mL/min Require a dosage adjustment of 50–100 mg every 12 h ( maximum daily dose 200 mg/d) For Ultracet , the recommendation in these patients is two tablets every 12 h Only 7% of tramadol and its metabolites is cleared by a 4-h dialysis. Dialysis patients can receive their dose on dialysis day

18. SPECIAL POPULATIONS Safety in pediatric population, during pregnancy, and in nursing mothers: Not established For acute pain in children as young as one-month-old consistently report that a 1–2 mg/kg single dose is safe and effective Classified as pregnancy risk factor C 1 % of the dose transferred via the placenta 0.1 % of the dose can be found in breast milk During labor it provides adequate maternal analgesia with no significant respiratory depression in the newborn

19. INDICATION FOR USE WHO recommends tramadol as a step 2 analgesic agent for a variety of painful conditions Malignant pain Osteoarthritic pain Low back pain Diabetic neuropathy Fibromyalgia Restless leg syndrome Postherpetic neuralgia Pain from surgical and dental procedures With NSAIDs to help control breakthrough pain

20. SIDE EFFECT PROFILE Intolerable side effects cause 20–30% of patients to discontinue tramadol Dizziness , lethargy, nausea, vomiting, and constipation are common complaints after the first week of usage. Complaints of nausea and vomiting may decrease with continued usage, but the incidence of other side effects such as dizziness, lethargy, headache, and constipation may fail to improve significantly The incidence of side effects may appear daunting, but it is similar to that of many opioids

21. TITRATION SCHEDULE A slow titration schedule improves tolerance for the medication Useful in chronic pain having a history of poor tolerance for medication or who is at increased risk for falls Balance must be struck between maximizing tolerance to the drug and achieving timely pain relief

22. TITRATION SCHEDULE

23. DRUG–DRUG INTERACTIONS Two most striking side effects are seizures and the serotonin syndrome

24. SEIZURES Seizures occurred in less than 1% of tramadol users Risk of seizures is increased with tramadol overdosage and as the number and dosage of other psychoactive medications are increased A ntidepressant agents (MAOI,TCAs, and SSRI), the neuroleptics, and other opioids Patients with spontaneous seizures with tramadol alone may be poor metabolizers of the drug

25. SEIZURES Avoid co-administration of tramadol with any medication that may lower the seizure threshold Avoid in pts with h/o seizures/epilepsy , head trauma, alcohol and drug withdrawal, and any other insult to the CNS Protective effect of co-administration of anticonvulsant medication with tramadol has not been established A seizure associated with tramadol should be treated with BZDs or barbiturates

26. Tramadol overdose Respiratory depression started at 500 mg Coma occurs at 800 mg The use of naloxone merely reversed some of the cardiorespiratory effects of tramadol and was associated with an increased risk of seizure activity

27. SEROTONIN SYNDROME Occur in co-administration with SSRI and the MAOI, that can increase CNS serotonin levels Serotonin syndrome should be suspected in any patient who develops an abrupt change in mental status accompanied by autonomic symptoms ( eg , fever, shivering, diaphoresis, nausea, vomiting, and diarrhea) other neurological changes ( eg , an increase in muscle tone, myoclonus, tremor, ataxia, agitation, hypomania, and hallucinations)

28. SEROTONIN SYNDROME Treatment: Cessation of the medication S ymptom management A dministration of antiserotonergic drugs such as cyproheptadine

29. WHY USE (OR AVOID) TRAMADOL Benefits of using tramadol instead of traditional opioids: Lower abuse potential and physical dependence Reduced side effects, such as constipation , respiratory depression , and sedation Rate of abuse with tramadol: less than 1/100,000 patients 97 % had a history of alcohol or drug dependence: caution in this patient population

30. WHY USE (OR AVOID) TRAMADOL Abstinence syndrome: When the drug is withdrawn abruptly, but the rate is reported at 1 per month per 100,000 cases Treated by reinstituting tramadol and gradually titrating the dose downward Methadone is effective in treating abstinence syndrome secondary to abrupt discontinuation of tramadol Patients with a true allergic reaction to codeine or morphine should use tramadol with caution

31. SUMMARY Mechanism not completely understood W orks b oth at the μ-opioid receptors and by inhibiting the reuptake of norepinephrine and serotonin in the CNS Proven effectiveness for moderate to moderately severe pain D oes not affect the prostaglandin cycle as do NSAIDs

32. summary Lower incidence of dependence and physical abuse than traditional opioids One-fifth as potent as oral morphine While the efficacy of morphine and tramadol increases with the size of the dose, dose-related toxicity limits the maximum potential of tramadol

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