Editor – The intranasal route for the administration of analgesia
appears to have great potential and the study by Kendal et al 1 should
encourage its use. However their comparison of intramuscular morphine with
intranasal diamorphine was pharmacokinetically flawed.
The primary problem was their interpretation of the data presently
available regarding the bioavailability of intranasal diamorphine. They
have assumed it to be 100% based on work by Cone et al,2 which reports
that the pharmacokinetic profiles of intranasal and intramuscular
diamorphine are equivalent. In contrast to this assumption Cone et al in
the same study, estimate that the potency of the intranasal route is
approximately 50% that of the intramuscular. This is supported by a second
study in which Skopp et al 3 looked at circulating levels of morphine–3-
glucuronide following intramuscular and intranasal administration of
diamorphine and demonstrated that about half the amount of diamorphine was
available from the intranasal route. This lower bioavailability may be as
a result of incomplete absorption, distribution into the oropharynx with
subsequent swallowing or hydrolysis of diamorphine as it passes through
the nasal mucosa. Both Skopp and Cone used dry powder and clearly
administration as a fine solution may result in a different
bioavailability.
Although intranasal and intramuscular diamorphine have similar
pharmacokinetic profiles, with peak plasma levels of diamorphine 2,3, and
peak levels of 6-acetyl-morphine 3 (one of the active metabolites)
occurring within five minutes this cannot be said of intramuscular
morphine. Probably as a result of its poor lipid solubility in comparison
to diamorphine, morphine has been reported as requiring up to twenty
minutes to achieve peak plasma levels by the intramuscular route.4 Peak
plasma levels do not correlate with peak effect, which occurs later
following redistribution to effector sites. This again is dependent on
lipid solubility and degree of ionisation at plasma pH and for morphine
has a half life of approximately 34 minutes.5
These facts mean that comparison between intranasal diamorphine and
intramuscular morphine over thirty minutes following administration is not
likely to give a good account of overall analgesia. The dose of
diamorphine chosen has an estimated potency about half that of the
morphine used. Its more rapid onset as judged by pain scores and falling
oxygen saturations is accounted for by the differing pharmacokinetic
profiles. The authors conclusion that 0.1 mg/kg of intranasal diamorphine
provides the same degree of pain relief as 0.2 mg/kg of intramuscular
morphine is therefore misleading. If speed of onset were the investigators
end point the intravenous route would have made a more appropriate
comparator. Regardless of the route of comparator a longer follow up
period would have allowed more meaningful assessment of the analgesic
efficacy of both dose and route.
James R Craig specialist registrar anaesthetics
Poole general Hospital, Longfleet Road, Poole, Dorset, BH15 2JB
1. Kendall JM, Reeves BC, Latter VS. Multicentre
randomised trial of nasal diamorphine for analgesia in children and
teenagers with clinical fractures. BMJ 2001; 322: 261-265
2. Cone EJ, Holicy BA, Grant TM, Darwin WD,
Goldberger BA. Pharmacokinetics and pharmacodynamics of “snorted” heroin.
J Analyt Toxicol 1993; 17: 327-337
3. Skopp G, Ganssmann B, Cone EJ, Aderjan R. Plasma
concentrations of heroin and morphine-related metabolites after intranasal
and intramuscular administration. J Anal Toxicol 1997; 21: 105-111
4. Stanski DR, Greenblatt DJ, Lowenstein E. Kinetics
of intravenous and intramuscular morphine. Clin Pharmacol Ther 1978; 24:
52-59
Rapid Response:
The pharmacokinetics of intranasal diamorphine
Editor – The intranasal route for the administration of analgesia
appears to have great potential and the study by Kendal et al 1 should
encourage its use. However their comparison of intramuscular morphine with
intranasal diamorphine was pharmacokinetically flawed.
The primary problem was their interpretation of the data presently
available regarding the bioavailability of intranasal diamorphine. They
have assumed it to be 100% based on work by Cone et al,2 which reports
that the pharmacokinetic profiles of intranasal and intramuscular
diamorphine are equivalent. In contrast to this assumption Cone et al in
the same study, estimate that the potency of the intranasal route is
approximately 50% that of the intramuscular. This is supported by a second
study in which Skopp et al 3 looked at circulating levels of morphine–3-
glucuronide following intramuscular and intranasal administration of
diamorphine and demonstrated that about half the amount of diamorphine was
available from the intranasal route. This lower bioavailability may be as
a result of incomplete absorption, distribution into the oropharynx with
subsequent swallowing or hydrolysis of diamorphine as it passes through
the nasal mucosa. Both Skopp and Cone used dry powder and clearly
administration as a fine solution may result in a different
bioavailability.
Although intranasal and intramuscular diamorphine have similar
pharmacokinetic profiles, with peak plasma levels of diamorphine 2,3, and
peak levels of 6-acetyl-morphine 3 (one of the active metabolites)
occurring within five minutes this cannot be said of intramuscular
morphine. Probably as a result of its poor lipid solubility in comparison
to diamorphine, morphine has been reported as requiring up to twenty
minutes to achieve peak plasma levels by the intramuscular route.4 Peak
plasma levels do not correlate with peak effect, which occurs later
following redistribution to effector sites. This again is dependent on
lipid solubility and degree of ionisation at plasma pH and for morphine
has a half life of approximately 34 minutes.5
These facts mean that comparison between intranasal diamorphine and
intramuscular morphine over thirty minutes following administration is not
likely to give a good account of overall analgesia. The dose of
diamorphine chosen has an estimated potency about half that of the
morphine used. Its more rapid onset as judged by pain scores and falling
oxygen saturations is accounted for by the differing pharmacokinetic
profiles. The authors conclusion that 0.1 mg/kg of intranasal diamorphine
provides the same degree of pain relief as 0.2 mg/kg of intramuscular
morphine is therefore misleading. If speed of onset were the investigators
end point the intravenous route would have made a more appropriate
comparator. Regardless of the route of comparator a longer follow up
period would have allowed more meaningful assessment of the analgesic
efficacy of both dose and route.
James R Craig
specialist registrar anaesthetics
Poole general Hospital, Longfleet Road, Poole, Dorset, BH15 2JB
1. Kendall JM, Reeves BC, Latter VS. Multicentre
randomised trial of nasal diamorphine for analgesia in children and
teenagers with clinical fractures. BMJ 2001; 322: 261-265
2. Cone EJ, Holicy BA, Grant TM, Darwin WD,
Goldberger BA. Pharmacokinetics and pharmacodynamics of “snorted” heroin.
J Analyt Toxicol 1993; 17: 327-337
3. Skopp G, Ganssmann B, Cone EJ, Aderjan R. Plasma
concentrations of heroin and morphine-related metabolites after intranasal
and intramuscular administration. J Anal Toxicol 1997; 21: 105-111
4. Stanski DR, Greenblatt DJ, Lowenstein E. Kinetics
of intravenous and intramuscular morphine. Clin Pharmacol Ther 1978; 24:
52-59
5. Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic
optimisation of opioid treatment in acute pain therapy. Clin Pharacokinet
1997; 33: 225-244
Competing interests: No competing interests