Morphine

Morphine

Morphine

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]

Dose requirements vary markedly, and patient response should be monitored frequently. In patients receiving palliative care, large doses may be required to control pain.

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.

Example of converting from immediate- to modified-release morphine:

If a patient has been taking morphine 15 mg orally 4-hourly and has required one breakthrough dose of morphine of 10 mg in the last 24 hours, then the total daily dose of modified-release morphine to be administered is 100 mg (see calculation below).

Calculation

15 mg 4-hourly = 90 mg (in 24 hours)
1 breakthrough dose of 10 mg = 10 mg
Total in 24 hours = 100 mg

Once-daily modified-release preparation = 100 mg once a day
OR
Twice-daily modified-release preparation = 50 mg twice a day

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.

Approximately [NB1] equipotent doses of morphine when administered by various routes (Table 1.6)

oral	30 mg
parenteral (SC, IM, IV)	10 mg
epidural	2 mg
intrathecal	200 micrograms
NB1: There is substantial variation in these ratios

Converting from immediate- to modified-release morphine preparations (Box 1.2)

Determine the total daily dose (the sum of all regular and breakthrough morphine [exclude morphine given for incident pain] given in the previous 24 hours). For preparations given twice daily, give half of the total daily dose 12-hourly. For preparations given once daily, give the total daily dose at the same time each day. Give the first dose at the same time as the last dose of immediate-release morphine to allow for its slow onset of action. [NB1]

NB1: This is not required when initiating modified-release oxycodone, as modified-release oxycodone contains an immediate-release component.

Note 1: Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003;349(20):1943-53.