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Hydromorphone
Hydromorphone is a derivative of morphine that is approximately five times as potent as
morphine. The main metabolite of hydromorphone is hydromorphone‐3‐glucuronide (H3G),
a structural analogue of morphine‐3‐glucuronide (M3G). Like M3G (see below) H3G is
dependent on the kidney for excretion, has no analgesic action and can lead to dose‐
dependent neurotoxic effects (Smith, 2000; Wright et al, 2001; Murray & Hagen, 2005).
Methadone
Methadone is a synthetic opioid commonly used for the maintenance treatment of patients
with an addiction to opioids and in patients with chronic pain. It is commercially available as
a racemic mixture of R‐ and L‐enantiomers, but it is the R‐enantiomer that is responsible for
most, if not all, its mu‐opioid receptor mediated analgesic effects (Lugo et al, 2005; Fredheim et
al, 2008).
It has good oral bioavailability (70% to 80%), high potency and long duration of action, and a
lack of active metabolites, (Lugo et al, 2005). It is also a weak NMDA receptor antagonist and
monoamine (5HT and noradrenaline [norepinephrine]) reuptake inhibitor and has a long and
unpredictable half‐life (mean of 22 hours; range 4 to 190 hours) leading to an increased risk of
accumulation (Weschules et al, 2008). Therefore it is of limited use for acute pain treatment.
Dose conversion is complex and depends on many factors including absolute doses of other
CHAPTER 4 opioids and duration of treatment.
Methadone is metabolised primarily by the cytochrome P450 group of enzymes including
CYP2B6, CPY3A4 and, to a lesser extent, CYP2D6 (Weschules et al, 2008). Concurrent
administration of other drugs that are cytochrome P450 inducers may increase methadone
metabolism and lower methadone blood levels (eg carbamazepine, rifampicin, phenytoin,
St John’s Wort and some antiretroviral agents). Conversely, drugs that inhibit cytochrome
P450 (eg other antiretroviral agents, some selective serotonin reuptake inhibitors, grapefruit
juice, and antifungal agents) may lead to raised methadone levels and an increase in adverse
effects (Fredheim et al, 2008). See Section 9.6.8 for interactions in patients with human
immunodeficiency virus (HIV).
High dose methadone has been associated with prolonged QT intervals (see below).
Morphine
Morphine remains the most widely used opioid for the management of pain and the standard
against which other opioids are compared. Morphine‐6‐glucuronide (M6G) and M3G, the main
metabolites of morphine, are formed by morphine glucuronidation, primarily in the liver. M6G
is a mu‐opioid receptor agonist that crosses the blood‐brain barrier more slowly than
morphine, contributes to morphine analgesia in patients with both normal and impaired renal
function, and has other morphine‐like effects including respiratory depression; M3G has very
low affinity for opioid receptors, has no analgesic activity, and animal studies have shown that
it may be responsible for the neurotoxic symptoms (not mediated via opioid receptors), such
as hyperalgesia, allodynia and myoclonus, sometimes associated with high doses of morphine
(Lotsch, 2005; van Dorp, Romberg et al, 2006; Dahan, van Dorp et al, 2008).
Clinical trials have investigated M6G as an analgesic agent after a variety of different types of
surgery. Two showed that M6G was as effective as morphine (Cann et al, 2002 Level II; Hanna
et al, 2005 Level II). In another two, in higher doses, it was more effective than placebo (Romberg
et al, 2007 Level II; Smith et al, 2009 Level II).
Excellent pain relief was also obtained after intrathecal administration of 100 or 125 mcg M6G
in patients after hip replacement surgery, but there was a high incidence (10%) of late
respiratory depression (9 to 12 hours after the dose was given) requiring treatment with
58 Acute Pain Management: Scientific Evidence
