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Survival and cessation in injecting drug users: prospective observational study of outcomes and effect of opiate substitution treatment

BMJ 2010; 341 doi: (Published 01 July 2010) Cite this as: BMJ 2010;341:c3172

If substitutes kill, we should treat with blockers

Kimber et al's abstracted conclusions are optimistic given the
paper's content: the paper should be considered in its entirety. Their
results show that long-term opiate substitution in Scotland has not been
effective in its primary aim of reducing injecting behaviour: in this
study increasing and prolonging that hazard. The authors assume in their
analysis procedures that long-term cessation prevents death despite 2/3 of
the reported deaths after (therapeutically delayed) cessation apparently
being due to Blood Borne Viruses, presumably acquired while injecting.
From the data it appears that 55 deaths occurred from drug overdose in
patients using prescribed opiates, giving an intervention mortality of
6.9%- 9.9% on the figures presented (it is not clear which denominator is
appropriate). Without a control group it is not possible to estimate the
relative risk of treatment: their evidence does not support the authors’
claim of “reduced mortality”. A mortality of one in 15 (perhaps 1:10)
patients would be high for a tertiary surgical intervention, let alone a
medical treatment delivered in primary care.

Put simply, in opioid neurochemistry miu stimulants (such as
Endorphins, Heroin and Methadone) act as the “accelerator” to overcome a
kappa stimulant “brake” on the feeling of well-being mediated in the
pleasure centres by Dopamine (kappa opioids act as presynaptic inhibitors
of Dopamine release), substitution treatment overcomes the brake by
pushing harder against it but treatments designed to reduce the braking
effect of endogenous kappa agonists (dynorphins, secreted as chronic
endogenous painkillers, often in response to abuse) are likely to be both
efficacious and safer.

Such approaches have been demonstrated, for example, Rothman et al
(1) describe the use of kappa blockade (permitting normal dopamine
release) in opiate detoxification by the co-administration of
Buprenorphine (miu agonist, kappa antagonist) and Naltrexone (miu
antagonist, kappa neutral) making use of Naltrexone’s greater affinity for
the miu receptor (Naloxone for example does not share this quality). Gerra
et al (2) showed the value of this approach to maintain abstinence in a
longer study. I have successfully maintained a patient on Naltrexone for
12 months by the adjuvant use of low frequency TENS at acupuncture “renal
points” to down regulate endogenous dynorphin as demonstrated by Han et al

The current medical pre-occupation with miu substitution is
apparently dangerous and ineffective in its primary aim of reducing
injecting behaviour; it might even be preventing the emergence of cheaper
and perhaps more efficacious blocking therapies, for example
detoxification by kappa blockade followed by TENS supported Naltrexone
administration or prolonged kappa blockade with Buprenorphine and

For the sake of patient safety in a particularly vulnerable patient
group we need urgently to review prescribing of opiate substitutes and
develop available alternative approaches, particularly those involving
pharmacological blockade.

1. Rothman RB. Gorelick DA. Heishman SJ. Eichmiller PR. Hill BH.
Norbeck J. Liberto JG. An open-label study of a functional opioid kappa
antagonist in the treatment of opioid dependence. Journal of Substance
Abuse Treatment. 18(3):277-81, 2000 Apr.

2. Gerra G. Fantoma A. Zaimovic A. Naltrexone and buprenorphine
combination in the treatment of opioid dependence. Journal of
Psychopharmacology. 20(6):806-14, 2006 Nov.

3.Han JS. Chen XH. Sun SL. Xu XJ. Yuan Y. Yan SC. Hao JX. Terenius L
Effect of low- and high-frequency TENS on Met-enkephalin-Arg-Phe and
dynorphin A immunoreactivity in human lumbar CSF. Pain. 47(3):295-8, 1991

Competing interests:
I am a General Practitioner whose practice area includes Muirhouse. We do not prescribe Methadone in General Practice. I have previously worked full time in a specialist addictions service.

Competing interests: No competing interests

08 July 2010
Andrew J Ashworth
GP Principal
Davidson's Mains Medical Centre, 5 Quality Street, Edinburgh EH4 5BP