Page 19 - Delaware Medical Journal - September/October 2020
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TREATMENT
Table 1: Pharmacodynamics/Kinetics of Tramadol 7,14:
Onset of action
Volume of distribution
Protein binding, plasma
Metabolism
Immediate release: Within 1 hour
Vd: IV: 2.6 L/kg (males); 2.9 L.kg (females)
~20 %
Extensively hepatic via demethylation (mediated by CYP3A4 and CYP2D6), glucuronidation, and sulfation
Peak effect: 2-3 hours
Pharmacologically active metabolite formed by CYP2D6 (M1; O-desmethyltramadol)
Bioavailability
Half-life elimination
Time to peak, plasma
Excretion
Immediate release: ~75%
Immediate release: 6.3 ± 1.4 hours; active metabolite (M1): 7.4 ± 1.4 hours; prolonged in elderly
Immediate release: ~2 hours; active metabolite (M1): 3 hours
Urine (~30% as unchanged drug; 60% as metabolites)
Extended release: ~85% - 95% (as compared to immediate release)
Extended release:
Capsules: ~ 10 hours; active metabolite (M1): ~11 hours
Tablets: ~7.9 hours; active metabolite (M1): 8.8 hours
Extended release: ~4 to 12 hours; active metabolite (M1): ~5 to 15 hours
the use of acetaminophen, non-steroidal
and cyclooxygenase-II inhibitors alone
is not enough to adequately manage
pain, but more potent opioids are not yet indicated. Initiation is also considered
in certain patient populations (i.e.
elderly, history of gastrointestinal bleed, cardiovascular risk factors, renal disease), may not be appropriate.4 From 2003 to 2009, the prescribing patterns for use in osteoarthritis doubled as emphasis shifted 5 The American College of Rheumatology guidelines conditionally recommend the
for knee osteoarthritis either alone or in
daily doses.6
There are currently two FDA-approved dosage forms of tramadol, including
an immediate and extended-release formulation. The immediate-release formulation is typically initiated at 25mg to 50mg every six hours as needed,
with a maximum dose of 400mg daily, and is intended for management of short-term pain lasting less than one week. Alternatively, the extended- release formulation can be initiated
at 100mg per day, and is intended for
those experiencing severe continuous pain lasting greater than one week. Due to its hepatic metabolism to an active metabolite, and primarily renal excretion, dosing adjustments must be considered to avoid toxicity.7 Clinical situations that would warrant reevaluation of the use
of tramadol in favor of an alternative for analgesia include renal impairment, severe respiratory disease, and concomitant such as benzodiazepines.
Tramadol's unique mechanism of
action has contributed to its appeal among providers as a useful analgesic alternative for the adequate management of musculoskeletal pain. It is an analogue of the opioid drug codeine, and along with its active metabolite, O-desmethyl tramadol (M1), it acts centrally to exert its analgesic effects via a number of different pathways. These pathways
are targeted by the synergistic action
of a racemic mixture of both (+) and
(-) enantiomers, which partially binds GABA and serotonergic receptors.8 Tramadol is also known to inhibit the reuptake of norepinephrine and serotonin, which are neurotransmitters intricately involved in the sensation of pain relief through action in the descending
inhibitory pain pathway.6,7 With respect
must be acted on enzymatically to its active metabolite. Unfortunately, there in the needed metabolite and others are hypermetabolizers. This provides for unreliable and unpredictable effects.4
reputation as being a safer opioid option, its mechanistic effects on norepinephrine and serotonin reuptake may be a key
to other opioid options, commonly implicated adverse effects include nausea, dizziness, vomiting, and dry mouth.
It has been suggested that tramadol is associated with a lower incidence of respiratory depression, constipation, sedation, and abuse potential.6 Despite these advantages, its action on neurotransmitters comes with a unique set of adverse reactions and drug interactions that must be considered. The most notable of these includes its seizure risk, which is a heightened concern in the setting of an overdose. This is further complicated by evidence that utilizing opioid antagonist naloxone in a tramadol overdose may exacerbate this risk. Caution should
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