Participants
This study employed an ambispective cohort design testing opioid exposed participants (illicit and non-illicit) and healthy non-substance using controls over a period of 24 months. Cohorts of participants with validated histories of illicit heroin use (HEROIN), stabilised methadone maintenance (METHADONE), chronic opioid prescriptions for pain (CHRONIC PAIN) and healthy controls (HEALTHY CONTROL) were recruited.
Heroin group (HEROIN)
The onset of action, peak effects, and duration of action vary with the different administration of heroin use. Patients experience heroin's effect within one or two minutes when injected intravenously and within fifteen to thirty minutes when injected intramuscularly. Heroin's peak therapeutic and toxic effects are generally reached within ten minutes when injected intravenously, within thirty minutes when injected intramuscularly or when snorted, and within ninety minutes when injected subcutaneously. Analgesic effects generally last between three and five hours (Borg &
Kreek, 1998).
Intravenously injected heroin creates a ‘rush’ or a sensation of intense pleasure that begins within one minute of the injection. This ‘rush’ is followed by a period of sedation that lasts about an hour. The initial ‘rush’ is likely due to heroin's high lipid solubility and rapid penetration to the brain (Leri, 2003). The half-life of heroin is between fifteen and thirty minutes (Borg & Kreek, 1998).
The presence of impurities and additives also limits heroin absorption through mucous membranes, thus limiting its ‘rush’ and ‘high’ when it is sniffed or snorted. It will also influence the neuropsychological performance of individuals taking additives that are neurotoxic and/or psychotropic (Schwartz, 1998).
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During the study period the mean percentage purity of illicit heroin was 40% of the total amount of the substance seized in Scotland (EMCDDA, 2008) and analysis of heroin seized in 2007-8 in Fife and Tayside revealed that caffeine and paracetamol were the most common added substances used to dilute the illicit heroin (Scottish Crime Drug Enforcement Agency, 2009). Other pharmaceutical products such as benzocaine, diazepam and phenacetin were also found in a minority of seized and analysed samples from the South East Scotland region in 2008 (Baldacchino et al., 2009).
When heroin is discontinued, the user generally experiences physical withdrawal symptoms. Withdrawal starts within 6-8 hours of the last administration. Withdrawal symptoms include: restlessness, insomnia, diarrhoea, vomiting, cold flashes with goose bumps, kicking movements and muscle and bone pains. Major withdrawal symptoms peak between 48 and 72 hours after the last dose and subside after about a week (DH, 2007).
Only male participants aged between 18 and 30 years entering for the first time a structured methadone maintenance treatment programme and attending Tayside and Fife Addiction Services between January 2007 and December 2009 were considered for inclusion in this study. The potential participants had confirmed histories of more than three years of regular, daily illicit opioid (usually heroin) use and met diagnostic criteria for opioid dependence syndrome according to DSM-IV (American Psychiatric Association, 1994; Appendix 4).
Participants were taking between 0.4 g and 1.5g of heroin intravenously daily or smoked heroin with an equivalent daily methadone dose of 40-120mg (Preston, 1996) and Table 2.1. They were also naïve to methadone and other types of prescribed opioids. The information on the participant’s drug history was subjective and there were no attempts to objectively validate the extent and magnitude of the participant’s drug exposure by measuring serum levels of the opioids taken.
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Measuring serum heroin and methadone levels was considered as not possible in the belief that it will increase the likelihood of attrition from the study and would have been practically be very difficult, in terms of venous access, to obtain the required two blood specimens. Also, any serum results obtained would not necessarily have provided a more accurate assessment of the optimal dosage of methadone (Bell et al., 1988).
Table 2.1: Illicit heroin conversion chart *.
Daily spend on
*Material adapted with permission from Preston, 1996. It is not possible to accurately predict equivalent doses in most cases. This is especially true for street drugs where purity is notoriously variable. It is also problematic to convert from one drug to another when the half lives are not
equivalent. Therefore this table is not intended to show absolute figures but possible range of dosages.
To standardise the pharmacological status of this HEROIN group and determine consistent stages of ‘withdrawal’ and optimal opioid dose a well established clinical tolerance testing procedure was used (Appendix 5). Tolerance testing was a single-blinded procedure that permitted the objective observation of individuals during stages of acute intoxication, withdrawal and subsequent stabilisation on a fixed dose methadone within a period of 7-14 days. Tolerance testing ensured that each participant took the dose that was considered optimal for them. Severity and quality of the opioid withdrawal symptoms were measured using the Clinical Opiate Withdrawal Scale (COWS) (Tompkins et al., 2009; Appendix 6).
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The participants were assessed on entry to tolerance testing which was between 3-5 hours after their last illicit dose so as to prevent any confounding results due to heroin intoxication. Then the same participants in the HEROIN group were invited to be retested in a state of opioid withdrawal and subsequently following a specified period of stabilisation with methadone. This assessment process took place within a 4 week period. This offered an opportunity to perform repeated neuropsychological testing during periods when illicit heroin is either present, absent or replaced by an alternative opioid (methadone) from the participant’s system. This approach also determined whether any deficits present represented a stable phenomenon or could be modified by different degrees of opioid receptor occupancy.
During the study period there were a total of 635 new treatment seeking individuals aged between 18 and 30 years old. Three hundred and seventy nine individuals were males and 295 of these cases presented with an opioid dependence syndrome. Eighty seven individuals were excluded due to presence of co-morbid severe mental health and/or physical conditions and a further one hundred and thirty six individuals were excluded due to co-occurring alcohol and/or benzodiazepine dependence. Another thirty eight individuals refused to participate leaving thirty six individuals that met the study criteria and who were invited to participate in this study. In summary half of all eligible cases who attended the Dundee and Fife Addiction Services in the two year study period were approached to participate in this study.
Twenty eight (50%) of these participants consented and were tested during illicit heroin use as the HEROIN group. Twenty six of these twenty eight participants were tested after their last intake of illicit heroin and subsequently retested more than twelve hours after their last intake of illicit heroin or any other opioids (in opioid withdrawal). Twenty four of the original twenty eight participants were tested after their last intake of illicit heroin, tested again in opioid withdrawal and then finally retested three weeks after stabilised on a daily methadone dose following tolerance testing (Appendix 7.1). One individual died just after initiating the methadone stabilisation stage.
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Methadone group (METHADONE)
Methadone is itself addictive and is only clinically prescribed for those who are clinically exhibiting physical opioid dependence especially withdrawal symptoms (DH, 2007). Methadone is dispensed as an oral solution (1 mg/ml) and the dose is adjusted according to the severity of the opioid dependence (Ward et al., 1999).
When administered at a therapeutic level to opioid dependent individuals, methadone produces no obvious psychotropic effects such as euphoria or sedation.
Methadone is well absorbed when taken orally and reaches a peak plasma concentration 2-4 hours after ingestion. Methadone has a plasma elimination half life of between 18-36 hours and, for this reason, a once a daily dose of methadone is thought to induce a steady state (Curran et al., 2001).
All male opioid dependent individuals aged between 18 and 30 years on methadone maintenance programme for more than 6 months, who showed retrospective and regular objective confirmation of the absence of illicit drug through weekly urine drug screen analysis and attending Fife Addiction Services between January 2007 and December 2009 were considered for inclusion in this study.
The potential participants had confirmed histories of more than three years of regular, daily illicit opioid (usually heroin) use and met a diagnosis of opioid dependence syndrome according to DSM-IV (APA, 1994). The participants have been taking between 0.4 g and 1.5 g of heroin intravenously daily or to have smoked heroin such that they have achieved a similar degree of drug exposure and clinically translating itself to an equivalent daily methadone dose of 40-120mg (Preston, 1996).
During the study period there were 2344 treatment seeking individuals who presented with opioid dependence and were prescribed methadone in Fife. One thousand five hundred and thirty four individuals were males with 524 of these individuals aged between 18 and 30 years old. Two hundred and ninety four individuals resided in Central Fife which included the Kirkaldy and Levenmouth areas.
One hundred and seventy four of these opioid dependent individuals were excluded
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due to the presence of co-morbid severe mental health and/or physical conditions and co-occurring alcohol and/or benzodiazepine dependence. Another seventy eight individuals were excluded since they did not show stability as stipulated by the study protocol. Overall forty two individuals fitted the inclusion criteria for the METHADONE group and were approached to participate in this study. Twenty nine (69%) agreed to participate and consented (Appendix 7.2).
Throughout the study period, participants were asked to take their prescribed dose of methadone in the morning (8-10am) so that this allowed testing to happen about four hours afterwards (2-5pm). This created a standardised approach to the timing of methadone intake and neuropsychological testing. The mean daily dose of methadone varied but was within the 40-120 mg range with a morphine equivalent mean of 147.41 (+/- 59.33) mg daily if we assume that the heroin purity of the samples used by the participants was 40%.
In order to determine that the results obtained were not time specific to the episode of treatment, eighteen out of the twenty nine participants were evaluated prospectively six months after their baseline neuropsychological test session.
Chronic pain group (CHRONIC PAIN)
All male non- opioid dependent individuals aged between 18 and 40 years with a history of more than three years of continuous prescribed opioids and attending the Tayside Pain Clinic between January 2007 and December 2009 were considered for inclusion in this study.
The potential participants had no history of ‘illicit’ opioid (e.g. heroin) use or methadone treatment and would not have met the criteria for a diagnosis of opioid dependence syndrome according to DSM-IV (APA, 1994).
During the study period there were a total of 303 treatment seeking individuals aged between 18 and 40 years who were referred to the Tayside Chronic Pain Clinic based
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at Ninewells Hospital and Medical School in Dundee. Forty one individuals who had a history of opioid medication for more than three years due to chronic non--malignant pain were approached to participate in this study. On further assessment three of these cases did not fit the eligibility criteria due to (a) one case having a recent diagnosis of malignancy, (b) one case leaving the catchment area and (c) another stopping his opioid medication due to an improvement in his chronic painful condition. In total twenty eight (72%) eligible individuals were approached and they all consented to participate (Appendix 7.3).
Normal control group (HEALTHY CONTROL)
The control group consisted of twenty eight healthy males matched for age and sex, with no history of chronic pain and/or illicit drug use or a lifetime continuous/regular prescription of opioids. This group were recruited from the general population residing in Fife and aged between 18 and 40 years.
General study design
The study design created an experimental model within which individuals either experienced different degrees of opioid receptor occupancy (HEROIN) or were receipt of chronic and stable prescribed opioids (METHADONE and CHRONIC PAIN).
Further, by including a cohort of non-heroin abusing individuals (CHRONIC PAIN) recruited from a pain clinic, one was able to identify the possible effects of drug adulterants and/or the ‘drug addict lifestyle’. By including a cohort of stable methadone maintained individuals (METHADONE) one was also able to retrospectively identify the possible contamination effect of previous illicit heroin use and prospectively test for deterioration and/or improvement.
The HEROIN group performed the neuropsychological tasks between three and five hours after smoking or injecting illicit heroin (baseline). They were then re-tested when experiencing opioid withdrawals ten to fifteen hours after stopping any opioid use as part of a tolerance testing procedure. This cohort was again re-tested between
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two and four weeks after the tolerance testing procedure when this cohort was adequately stabilised on a daily dose of methadone. They were therefore tested on three occasions.
The METHADONE group performed the neuropsychological tasks between 4-6 hours of taking their last stable dose of methadone (baseline). They were re-tested again six months after their initial baseline test period. They were therefore tested on two occasions.
The CHRONIC PAIN group performed the neuropsychological tasks between 4-6 hours after taking their chronic stable dose of opioid medication. They were therefore only tested at baseline.
The HEALTHY CONTROL group was tested once at baseline (Table 2.2).
Table 2.2: Study procedures.
Testing Sessions
Illicit or licit opioids
Opioid withdrawal
2-4 weeks on
methadone
6 months on methadone
HEROIN † † † —
CHRONIC PAIN † — — —
METHADONE † — — †
HEALTHY CONTROL — — — —
†= tested; —= not tested
A two staged screening and assessment process was used. The identified individuals were approached by their keyworkers in order to seek interest in participation to this study. Informed written consent to participate in the study was obtained from this group in accordance with the guidelines from the Tayside Committee on Medical Research Ethics. Consent was subsequently obtained after the first meeting with the researcher (Appendices 8 & 9).
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Inclusion and exclusion criteria
Criteria for inclusion and exclusion to this study was based on the methodological limitations and confounding factors identified in Chapter 1.
The inclusion criteria were:
Male gender
Males older than 18 years and younger than 30 years. In the CHRONIC PAIN and HEALTHY CONTROL groups the age limit was increased to 40 years.
Presenting with opioid dependence syndrome in the drug using population (HEROIN and METHADONE groups) and not in the CHRONIC PAIN group,
More than three years of daily opioid use.
All individuals who presented with the following conditions were excluded. They were:
Female gender.
Males younger than 18 years and older than 30 years in the METHADONE and HEROIN groups only.
Intoxication due to drug and/or alcohol use.
Co-occurring severe physical problems with acute confusional state.
Presenting with opioid dependence syndrome in the chronic pain group.
Co-occurring benzodiazepine, psycho-stimulant and alcohol dependence.
History of Acquired Immunodeficiency Syndrome (AIDS) or associated HIV infection.
Post Trauma Amnesia.
Recent and past overdose episodes needing Cardio Pulmonary Resuscitation (CPR).
Bipolar or severe depressive mood disorder.
Schizophrenia.
Post Traumatic Stress Disorder (PTSD).
Attention Deficit Hyperactivity Disorder (ADHD) (Adult and Childhood).
History of confirmed epilepsy.
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Neurological (sensory and motor) impairment.
Previously determined learning disability (Intelligence Quotient (IQ) lower than 80).
Inability to understand English.
Screening clinical instruments
Eligible and consented individuals were then screened using a battery of validated instruments and their psychiatric, addiction and general practice case records accessed.
The screening clinical instruments included the Mini International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998) and Post Trauma Questionnaire (PTQ) (McMillan et al., 1996) (Appendices 10 & 11).
A drug urine analysis screen was also conducted to validate a three or four day history of opioid (usually heroin) intake and also absence of any other illicit drugs such as amphetamine, cocaine, benzodiazepine and cannabis (Quantum Diagnostics Ltd) as part of the screening process.
Assessing and screening for mental health related problems/illnesses: Mini International Neuropsychiatric Instrument (MINI) version 5.0
The M.I.N.I. is a brief structured diagnostic and screening interview for the major Axis I psychiatric disorders in DSM-IV and ICD-10 (Sheehan et al., 1998). Validation and reliability studies have been done comparing the M.I.N.I. to the Structured Clinical Interview for DSM III-R Patients (SCID-P) and the Composite International Diagnostic Interview (CIDI) with results showing that the M.I.N.I. has acceptably high validity and reliability scores (Sheehan et al., 1997).
It elicits all the symptoms listed in the symptom criteria for DSM-IV and ICD-10 for 15 major Axis 1 diagnostic categories, one Axis II disorder. It uses a decision tree logic which is consistent with DSM-IV and ICD-10 diagnostic algorithms. The MINI includes
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a psychiatric assessment of current diagnoses of PTSD, panic disorder, generalized anxiety disorder, social phobia, major depression, psychotic disorders, substance (drug and alcohol) abuse or dependence, ADHD, antisocial personality, somatisation and adjustment disorders (Sheehan et al., 1998).
With an administration time of approximately 15 minutes, the M.I.N.I. is the structured psychiatric interview of choice for psychiatric evaluation and outcome tracking in clinical psychopharmacology trials and epidemiological studies.
Participants’ views of MINI were also positive (Amorin et al., 1998). It was considered comprehensive enough to cover all patient symptoms and at the same time not being unduly lengthy.
Assessing and screening for episodes of head injury and other cerebral insults: Post Traumatic Amnesia Questionnaire (PTQ)
Post-Traumatic Amnesia Questionnaire was considered to be the best single indicator of the severity of closed head injury (Russell & Smith, 1961).The duration of post-traumatic amnesia was taken to be the interval between injury and the patient regaining continuous memory for day to day events. The interview was structured by using notes in case records and dates of special events (Appendix 11) to establish landmarks in the acute stage after the head injury (McMillan et al., 1996).
Objective measurement of substance misuse: urine analysis drug screening method Recent substance use may result in symptoms that are indistinguishable from psychiatric symptoms. Accurate interpretation of the screening tests within a clinical setting, alongside other relevant information, remains the key to the usefulness of any test (Simpson et al., 1997; Neale & Robertson, 2003).
Quantitative accuracy usually demands the collection of a blood, hair or saliva samples. The advantage of hair sampling is its reflection of weeks/months rather than hours of recent use (Wolff et al., 1999).All the above tests are expensive and analysis of urine is currently the biological tool of choice for qualitative detection of illicit drug
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use, becoming a common objective adjunct in the validation and reliability of substance misuse and mental health screening and/or diagnostic instruments (Wolff et al., 1999). The significant advantage of urine for drug testing is that biologically urine is generally available in sufficient quantity and the drugs or their metabolites tend to be present in relatively high concentrations (Moffat et al., 1986).
The procedure used in this study was for analysis for drugs of misuse undergoing an initial screening test using self-contained drug testing kits for on-site testing
(Armbruster & Krolak, 1992; Jenkins et al., 1995). The kit testing for cannabis, opioids, benzodiazepine, amphetamine and cocaine onsite was used for this study (Quantum Diagnostics Ltd and Illustration below).
The same urine sample were then sent to the laboratory for another screening process using an automated Enzyme-Mediated Immunoassay (EMIT) or Enzyme Linked Immunosorbent Assay (ELISA) to classify the type of drug (i.e.
opioid, benzodiazepine, etc.) (Wilson et al., 1994). In the event of a positive finding a thin-layer (TLC), gas (GC) or liquid (LC) chromatography would be used for confirmation of a specific drug in the sample (i.e. morphine, codeine etc) (Braithwaite et al., 1995; Simpson et al., 1997).
Diagnostic clinical instruments
The diagnostic clinical instruments used for this study include the MINI (Sheehan et al., 1998), the Maudsley Addiction Profile (MAP) (Marsden et al., 1998a & 1998b), and the Fagerström Test for Nicotine Dependence (FTND) (Fagerström & Schneider, 1989) (Appendices 12 & 13). Drug urine samples to confirm a recent history of opioid (heroin) intake and absence of any other illicit drugs. (Quantum Diagnostics Ltd) were analysed throughout the study period from all cohorts participating including the HEALTHY CONTROL group. The Clinical Opiate Withdrawal Scale (COWS) quantified the level of opioid withdrawal in the HEROIN group.
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Assessing diagnosis of opioid dependence syndrome: Mini International Neuropsychiatric Instrument (MINI) version 5.0
The MINI is a brief structured diagnostic and screening interview for the major Axis I psychiatric disorders in DSM-IV and ICD-10 (Sheehan et al., 1998). Description of the MINI is provided in the previous section. Diagnosis of opioid dependence, use and
The MINI is a brief structured diagnostic and screening interview for the major Axis I psychiatric disorders in DSM-IV and ICD-10 (Sheehan et al., 1998). Description of the MINI is provided in the previous section. Diagnosis of opioid dependence, use and