162 ANALGESICS AND THE CONTROL OF PAIN
NALOXONE
Naloxoneis a pure competitive antagonist of opioid agonists
atμ-receptors. It is given intravenously, the usual dose being
0.8–2.0 mg for the treatment of poisoning with full opiate ago-
nists (e.g. morphine), higher doses (up to ten times the recom-
mended dose, depending on clinical response) being required
for overdosage with partial agonists (e.g. buprenorphine,
pentazocine). Its effect has a rapid onset and if a satisfactory
response has not been obtained within three minutes, the dose
may be repeated. The action of many opioids outlasts that of
naloxone, which has a t1/2of one hour, and a constant-rate
infusion of naloxonemay be needed in these circumstances.
Naloxoneis used in the management of the apnoeic infant
after birth when the mother has received opioid analgesia
during labour. Naloxonecan precipitate acute withdrawal
symptoms in opiate-dependent patients.NALTREXONE
Naltrexoneis an orally active opioid antagonist that is used in
specialized clinics as adjunctive treatment to reduce the risk of
relapse in former opioid addicts who have been detoxified. Such
patients who are receiving naltrexonein addition to supportive
therapy, are less likely to resume illicit opiate use (detected by
urine measurements) than those receiving placebo plus support-
ive therapy. However, the drop-out rate is high due to non-com-
pliance.Naltrexonehas weak agonist activity, but this is not
clinically important, and withdrawal symptoms do not follow
abrupt cessation of treatment. Treatment should not be started
until the addict has been opioid-free for at least seven days for
short-acting drugs (e.g. diamorphineormorphine), or ten days
for longer-acting drugs (e.g. methadone), because it can precipi-
tate a severe and prolonged abstinence syndrome. Naltrexone
has not been extensively studied in non-addicts, and most of the
symptoms that have been attributed to it are those that arise from
opioid withdrawal. Its major side effects are various type of rash.ANALGESICS IN TERMINAL DISEASE
The relief of pain in terminal disease, usually cancer, requires
skilful use of analgesic drugs. There are several important
principles:- Non-opioid analgesics minimize opioid requirement. The
World Health Organization (WHO) has endorsed a simple
stepwise approach (WHO ‘pain ladder’), moving from
non-opioid to weak opioid to strong opioid. For mild
pain,paracetamol,aspirinorcodeine(a weak opioid) or a
combined preparation (e.g. cocodamol) is usually satisfactory. - Morphine(or a congener) is the key treatment for severe
pain. It is important to use a large enough dose, if
necessary given intravenously, to relieve the pain
completely. There is a wide range in dose needed to
suppress pain in different individuals. - Drug dependence is not a problem in this type of patient.
- It is much easier to prevent pain before it has built up than
to relieve pain when it has fully developed.
Pharmacokinetics
After oral dosage, the peak blood concentration is achieved
within about four hours, and once-daily dosing is practicable
because of its long half-life.
CODEINE
Use
Codeineis the methyl ether of morphine, but has only about
10% of its analgesic potency. (Dihydrocodeineis similar, and
is a commonly prescribed alternative.) Although codeineis
converted to morphine, it produces little euphoria and has
low addiction potential. As a result, it has been used for many
years as an analgesic for moderate pain, as a cough suppres-
sant and for symptomatic relief of diarrhoea.
Adverse effects
Common adverse effects involve constipation, nausea and
vomiting.
Pharmacokinetics
Free morphinealso appears in plasma following codeine
administration, and codeineacts as a prodrug, producing a
low but sustained concentration of morphine. Individuals
who are CYP2D6 poor metabolizers convert much less
codeinetomorphine, and consequently experience less, if any,
analgesic effect.
PENTAZOCINE
Pentazocineis a partial agonist on opioid receptors (especially
κ-receptors, with additional actions on σ-receptors, which
result in hallucinations and thought disturbance). It also
increases pulmonary artery pressure. Its use is not recom-
mended.
BUPRENORPHINE
Use
Buprenorphineis a partial agonist. It is given sublingually. It
antagonizes full agonists and can precipitate pain and cause
withdrawal symptoms in patients who are already receiving
morphine. It has recently (in the USA, as well as in the UK)
become more widely used in the treatment of opiate with-
drawal as an alternative to methadone.
Pharmacokinetics
Like other opiates, buprenorphineis subject to considerable
pre-systemic and hepatic first-pass metabolism (via glu-
curonidation to inactive metabolites), but this is circumvented
by sublingual administration.
OPIOID ANTAGONISTS
Minor alterations in the chemical structure of opioids result in
drugs that are competitive antagonists.