S Hepburn, J Harden, JHK Grieve*, J Hiscox
Departments of Emergency Medicine, and *Forensic Medicine, Aberdeen Royal Infirmary
SMJ 2005 50(3): 131-133
Introduction
Tricyclic antidepressants (TCAs) abuse remains a common presentation to Accident and Emergency departments, usually in the context of deliberate self harm and overdoses. The authors present three fatal case studies of intravenous drug abusers who have subsequently found to be taking TCAs as well as intravenous street heroin. With the well known interaction and synergistic effect of opiates and TCAs the authors believe that deliberate misuse of TCAs is not unlikely by the intravenous drug abusing population.1-4
Case reports
Case 1
The first case is a 18-year-old male known to be an intravenous drug abuser who had shared a bag of street heroin with his brother. His brother had an equal quantity of the ‘hit’ intravenously but the victim had collapsed and found to be dead on the arrival of paramedics some time later. He was known to be prescribed doxiepin from his GP for concurrent depression, and interestingly the police investigation later revealed that ‘. . . more tablets were missing from the bottle that would be expected.’ Post mortem bloods revealed a blood concentration level of free morphine 0.34mg/l, diazepam 0.77mg/l and doxiepin 1.68mg/l.
Case 2
The second case was a 49-year-old male, again known to be an intravenous drug abuser and prescribed amitriptyline by his GP for concurrent depression. Post mortem bloods revealed a blood morphine concentration of 0.75mg/l, codeine level of 0.01mg/l, amitriptyline level of 1.14mg/l and nortriptyline level of 1.01mg/l.
Case 3
The third case was a 28-year-old female, again known to be an intravenous drug abuser to family and friends. She was found dead in a flat after a party the previous evening. Subsequent post mortem investigation and toxicology revealed a free morphine level of 0.28mg/l, diazepam 0.55mg/ l and amitriptyline level of 1.45mg/l. Interestingly she was not recorded as being prescribed any antidepressants by her GP and the source of these drugs is not known.
Discussion
Tricyclic antidepressants (TCAs) have been prescribed for decades. They have two main properties, which are analgesic and antidepressant, both of which have been well documented over years of research.1,2 The interaction between opiates and TCAs has been recognised, and exploited, by chronic pain teams since the early 1960s and remains today a common solution for chronic pain patients.4,5
Because they are so frequently used, a lot of research has been done looking at the specific mechanism for the synergistic effect of opiates and TCAs and their use. TCAs main effect on their own is both pre-synaptically and postsynaptically. Pre-synaptically, TCAs block the re-uptake of sertonin, norepinepherine and dopamine. The postsynaptically effect seems to depend on the exact type of antidepressant used, amitriptyline for example interacts with muscarinic, cholinergic, histamine, substance P and serotonergic receptors. The interaction with opiates appear to centre around the effects on sertonin and other neurotransmitters, which activates the endogenous opioid system and increase endorphin levels around the hypothalamus. TCAs also appear to increase the plasma free level - and hence the bioavailability - of opiates.1,2,3
The other toxic effects of TCAs should not be forgotten also. These include the direct myocardial and cardiac toxicity, mediated by changes to membrane sodium and potassium channels and systemic acidosis.
There is therefore a very clear link between the potentiating effects of opiates by TCAs, and intravenous drug abusers can source these drugs from a number of places. Anyone who has contact with people who abuse drugs is aware that they can be a highly demanding, and oftenmanipulative group of patients. They present with a wide variety of problems to both primary care and hospitals, including skin problems, blood borne infections, cardiovascular or respiratory problems and mental health issues. Depression is a common presentation, and it is often difficult to distinguish the precipitating cause. That is to say, whether the depression precedes the drug misuse, as a direct result of their drug use, a result of drug addiction but unable to obtain drugs, or as a side effect of any other drugs of abuse such as benzodiazepines.
The vast majority of depression presenting to primary care doctors are treated by the same primary care doctor, rather than specialist referral, and will often involve the prescription of an antidepressant. Even when an intravenous drug abuser presents to their GP requesting prescriptions of benzodiazepines, up to one third of are prescribed an antidepressant instead.8 Of all intravenous drug abusers, one half will use antidepressants at any stage in their drug career and at any one time one quarter will be taking antidepressants. Of all patients taking antidepressants half will be prescribed tricyclic antidepressants. The procurement of tricyclic antidepressants was considered “easy” by 88% of intravenous drug abusers with 76% getting from their doctor and 16% from family or friends. Indeed one fifth of all prescribed TCAs are subsequently sold by the patient illegitimately making them readily available for purchase “on the street”.8
When reviewing the incidence of drug overdoses, in the patient groups who had been taking tricyclic antidepressants and abusing intravenous opiates there was a significantly higher lifetime risk of overdose than a control group of 68% vs 47% (with 95% confidence intervals) and in the preceding six months a risk of 44% vs 14% (with 95% confidence intervals)(8).
In England, Cheeta et al reviewed the drug related deaths for 1998-2000 and found that of 4167 deaths, 468 involved antidepressants. Of these the majority were deliberate overdoses and suicides, but of the deaths involving more than one drug 10% involved heroin and tricyclic antidepressants. Interestingly, of this group of deaths one in five were thought to be accidental rather than deliberate.9
In conclusion therefore, there is a clear link between the potentiating effects of tricyclics antidepressants on opiates. With this knowledge, it is likely that these classes of antidepressants are being deliberately misused in order to prolong the “hit” from injected opiates. Indeed, Dorman et al in a letter to the BMJ reported a high rate of misuse of dothiepin by their patients attending the Drug Treatment Centre in Dublin.10 They found that 19% of patients (19/ 99) who were not prescribed tricyclic antidepressants had either TCAs or metabolites in their urine sample. An anonymous questionnaire revealed an increase in euphoria and pleasant auditory and visual hallucinations. As far back as 1978, Cohen et al cautioned about the misuse of amitriptyline in after finding 25% of their patients on a methadone maintenance program were deliberately misusing tricyclic antidepressants “with the purpose of achieving euphoria”.11 There is also the group of drugs users who may be prescribed TCAs by their GPs for treatment of any genuine concurrent depression, who will subsequently be at risk of exaggerated side effects of their heroin or methadone. All of the information regarding drug interactions is readily available to any user of the internet, and indeed are freely listen in a host of pharmacology text. Indeed, the effects of combining TCAs and opiates are openly documented in Martindales for example. We should not underestimate the knowledge and resources available to the drug using population in any way. Information about “howto- take-drugs” is frequently passed between drug users, and once this association is recognised it is likely the knowledge would be shared rapidly amongst other users.
Whilst interactions between opiates and newer generation of antidepressants such as SSRIs are not clearly known, it would appear safer to prescribe these medicines to patients known to abuse drugs, and we urge drug screening on all patients suspected of drug misuse prior to starting treatment.
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