Tramadol is a centrally-acting analgesic with a dual mechanism of action, binding weakly to μ-opioid receptors and inhibiting the reuptake of norepinephrine and serotonin. It has fewer side effects than other opioids like morphine and a lower risk of abuse and dependence. Tramadol is effective for moderate to moderately severe pain and does not affect the prostaglandin cycle like NSAIDs. While less potent than morphine, tramadol has a better side effect profile and safety margin at therapeutic doses.

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. Weak 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
Dual mode of action:
1. Binds 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
 Elderly 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
Antidepressant 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
•Symptom management
•Administration 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
 Works both 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
 Does 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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