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. 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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