Pharmacology Notes

Morphine is an agonist at all opioid receptors, particularly the mu receptor. It is the prototypical opioid, and can be given via many routes of administration. After oral use, morphine is well absorbed; however, significant first-pass metabolism reduces the bioavailability to approximately 30% of the original dose. As a consequence, oral administration results in a greater production of metabolites than does parenteral administration. The metabolites comprise mainly morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). They are both renally excreted and therefore accumulate in patients with renal impairment. M6G is a potent analgesic and contributes to the analgesic effect when morphine is given long term. M3G has no analgesic activity itself and may antagonise the analgesic activity of morphine and be responsible for neurotoxic symptoms (hyperalgesia, allodynia, seizures, myoclonus). The elimination half-life of morphine is 1.5 to 2 hours, and the duration of analgesic effect is 3 to 6 hours.

Morphine can be given by oral, subcutaneous, intramuscular, intravenous, epidural, intrathecal and intracerebroventricular routes. See Table 1.6 for approximately equipotent doses when administered by various routes (note that there is substantial variation in these ratios). The oral route is preferred for long-term administration

Tolerance can develop rapidly, particularly in intravenous drug users in the absence of pain. The development of tolerance does not, however, prevent effective long-term use of morphine or other opioids in patients with chronic pain in palliative care. For chronic noncancer pain, the long-term prescribing of opioids is more controversial, and guidelines for their use have been established. [Note 1]

In circumstances where regular use of morphine is appropriate, modified-release morphine preparations are convenient when the 24-hour dose (total daily dose) has been established. Modified-release preparations reduce peaks and troughs in morphine plasma concentrations, thus reducing drowsiness, nausea and breakthrough pain; they avoid the need for drug administration during the night and are more palatable than oral mixtures. Problems can arise from the use of modified-release opioids if they are used ‘as required’ rather than regularly, if they are used for pain that is not chronic, or if the tablets are chewed rather than being swallowed whole. Factors to consider when converting from immediate-release morphine to modified-release morphine preparations are given in Box 1.2.

Adverse effects, interactions and precautions: 

The most common adverse effects of long-term use of morphine are sedation, nausea, vomiting, constipation and sweating. Nausea and vomiting usually settle over the first week of treatment. Constipation can be minimised by regular use of laxatives from the time morphine is initiated. Respiratory depression can occur in opioid-naive patients, in those with severe respiratory disease and in the presence of other sedatives; it does not generally occur with maintenance dosing. Asthma and urticaria can occasionally occur due to the release of histamine. See also Table 1.5.