Wet Brain: Alcohol and the Brain - delirium, confabulation, amnesia, and collapse.
In this seminar, Dr Paul Haber looked at the ways alcohol affects the brain, both “direct” effects (intoxication, dependence, withdrawal, hallucinosis and sleep disturbance) and “indirect” effects, ranging from Wernicke-Korsakoff Syndrome to head injury, stroke, intracranial haemorrhage and epilepsy.
The corpus callosum, cerebellum and mamillary bodies are areas of the brain most prone to the effects of alcohol, but indeed the whole brain is sensitive to the effects of alcohol. The extent of this susceptibility is perhaps best seen in the globally impaired brain development of the foetal alcohol syndrome.
(Dr Haber reminded us to be vigilant: FAS is often first diagnosed in adulthood, and that even late identification and management may improve people’s functioning in life.)
Multiple pathology is the rule rather than the exception, even when only alcohol is the injurious agent (as opposed to injury, cerebrovascular disease, hypertension, thiamine deficiency etc).
While dopaminergic and opioid neurochemical in the “brain reward pathways” underlie the phenomena of dependence and craving, the syndrome of alcohol withdrawal results from alcohol’s effects at ligand-gated ion channels, especially GABA-A & NMDA receptors. Adaptive changes in response to chronic alcohol consumption, including desensitization of GABA-A and up-regulation of NMDA receptors, lead to the hyperexcitable state of the CNS in alcohol withdrawal.
Alcohol withdrawal seizures are an important example of this CNS hyperexcitability. They tend to occur in the first 24 hours of alcohol withdrawal and 90% occur within 48 hours. They occur in 10% of hospital series of alcohol withdrawal (they may be less common in community practice). Risk is proportional to the prior level of alcohol consumption. They are generalised tonic-clonic in 95%, and most are uncomplicated and self limiting, however they are multiple in 25%. The EEG is normal in 90% of cases. Seizures are more likely to happen in people who are metabolically unwell. Alcohol also predisposes to seizures in epilepsy and to brain injury which can be a cause of seizures.
Benzodiazepines are effective treatment for alcohol withdrawal (see Cochrane review, Amato et al 2010). Further, in a study of chronic alcohol users who presented to Boston emergency departments after a witnessed, generalized seizure, treatment with intravenous lorazepam was associated with a significant reduction in the risk of recurrent seizures (D’Onofrio et al, N Engl J Med 1999 340:915-9.)
We were reminded that in ambulatory settings, claims to have had alcohol-related seizures may more commonly come from people trying to get benzodiazepines, than from true cases.
Dr Haber mentioned alcoholic hallucinosis, a rare syndrome (0.6% hospitalised alcoholics; Soyka 2008) which needs to be distinguished from the hallucinations of delerium tremens (DTs) and also from alcohol-related psychotic disorder. They are typically auditory hallucinations, and may be accompanied by paranoia, but with preserved insight. The key to diagnosis is that they occur with a clear sensorium. They may occur while drinking and persist during withdrawal, but the majority settle with abstinence. (Dr Peter Tucker however reminded us that most cases of people hearing voices while drinking alcohol will be chronic schizophrenics, as this condition is relatively common and many schizophrenics “self-medicate” with alcohol and other drugs).
Another organic brain syndrome related to alcohol is hepatic encephalopathy. There may be impaired cognitive function, but importantly, this is reversible in early stages, and treatment with lactulose is effective. Most people with hepatic encephalopathy are jaundiced, but bilirubin excretion may be preserved: the mechanism of encephalopathy involves porto-systemic shunting.
The essential neuropathology of direct alcohol-related brain damage is white matter atrophy with reduced brain weight. Myelination and axonal integrity are involved. There can also be grey matter neuronal loss, and large neurons are most susceptible, the same neurons affected by Alzheimer’s disease and ageing. These changes are reversible in experimental animals with alcohol abstinence.
Alcohol is toxic to the brain independent of thiamine deficiency, but the latter probably causes most of the problem we see in clinical practice, including the Wernicke-Korsakoff syndrome (WKS).
Thiamine pyrophosphate is a co-factor in oxidative decarboxylation of α-keto acids. Plant seeds are the major dietary source, but thiamine is removed in processing of white flour and rice. Dr Haber mentioned Dr Clive Harper, of Sydney University, who lead the battle to supplement Australian flour with thiamine, leading to a reduced incidence of
deficiency states.
Dr Harper’s recent review of “The neuropathology of alcohol-related brain damage” (Alcohol. 2009 Mar-Apr 44(2):136-40.) is available free on Pubmed at http://www.ncbi.nlm.nih.gov/pubmed/19147798
Thiamine is highly water soluble, and is lost in cooking. Average requirements are 1 mg/day. Heavy users of alcohol have reduced dietary intake, reduced absorption and increased requirements, partly owing their unbalanced, carbohydrate heavy diets.
The classic triad of Wernicke’s enecephalopathy is present in only 10% of cases, so many cases probably go undiagnosed, or are first diagnosed at autopsy. Confusion is the most common manifestation, with ataxia present in 23% and nystagmus in 29% (with or without horizontal gaze or other palsy)
Wernicke’s is a medical emergency: rapid treatment with parenteral thiamine is highly successful, as the changes are largely reversible, while delayed treatment may result in permanent severe disability.
A Cochrane review concluded there is insufficient evidence to guide treatment with thiamine (other than to say 200mg better than 5mg!). However, the usual practice is to give it prophylactically in all alcohol users admitted to hospital, as 100mg tds 3-5 days, then 100mg daily until abstinent >3 months (which may mean indefinitely). Thiamine is given parenterally if the patient is unwell or receiving IV fluids, and parenteral treatment should always commence prior to IV glucose, as a carbohydrate load may precipitate Wernicke’s enecephalopathy. If there is any suggestion of confusion or WKS, thiamine should be given 100mg tds by IVI or IMI.
The chronic phase of the Wernicke-Korsakoff syndrome, Korsakoff’s psychosis, is dense anterograde amnesia with confabulation, apathy and gross functional impairment, reflecting damage to the anterior nucleus of thalamus. Estimated prevalence is 12% in alcoholics, so it is still common. It may overlap with features of alcohol-related cerebrocortical degeneration, including frontal lobe syndrome (with impaired abstract thinking and executive function, disinhibition and personality change) and pre-senile dementia.
Diagnosis requires a history of harmful alcohol use, and exclusion of other explanations for symptoms (eg diazepam use). Bed-side tests of cognition like the Mini Mental State Examination are usually sufficient, however MMSE is not sensitive to early disease (Manning et al 2007). The Clock test is moderately sensitive and specific and very quick and very cheap! (Pinto and Peters Dement Geriatr Cogn Disord. 2009 27(3):201-13). Formal neuropsychiatric testing is useful to determine functional capacity and in doubtful cases, but is costly, time consuming and difficult to do in this population. Dr Haber considers it is over-ordered.
The etiology of alcohol-related cerebellar damage, like Wernicke’s, has a nutritional component, and these syndromes may overlap, or even form a continuum; but unlike Wernicke’s, cerebellar damage evolves subacutely over months & is often not fully reversible. Characteristically, there are wide-based stance and gait, with the legs worse affected than the than arms, while speech and ocular movements are relatively spared. The cerebellum also involved in perception and executive functions and memory, so cerebellar damage may contribute to cognitive deficits. Treatment involves alcohol abstinence, thiamine and multivitamins.
Alcohol is associated with stroke by a J-shaped curve, like cardiovascular disease. Moderate consumption lowers stroke risk but there is 4-5 times increased risk at high levels of consumption. Heavy drinking is associated with smoking and with hypertension. Brain haemorrhage (arachnoid, intracranial and subdural) needs to be considered in any confused or obtunded person with a history of harmful alcohol use. A rare but important alcohol-related problem is central pontine myelinolysis, causing quadriparesis and locked in syndrome, when hyponatremia is too rapidly corrected. Diagnosis is confirmed by MRI.
Finally, an estimated 50-75% of traumatic brain injury is associated with substance use, but 50% of cases do not present to hospital, and previous brain injury is often overlooked in clinical history and examination. Alcohol use is associated with poorer prognosis and delayed recovery from brain injury which in turn is associated with poor outcomes of alcohol treatment.
Indeed, most “talking therapy” is cognitively intensive and may be beyond the capacity of people with alcohol-related brain damage, in terms of reasoning skills, attention skills and memory. One needs either to adapt the program or discontinue it. Rehabilitation services present a particular challenge: the patient who most needs this treatment is least likely to benefit from it.
CASE STUDIES:
In the second half, three Case Studies of the Bach Siblings were worked through, to show the need to consider a range of causes for collapse, confusion, and ataxia in heavy drinkers.
Wilhelm Friedrich Bach, a 58 year old male disability pensioner was brought in to the Emergency Department by ambulance, hypothermic (oral temperature 34) after being found lying supine on the footpath in an inner city street, smelling of alcohol. He had been drinking daily since the age of 25.
He was conscious with no neurological deficit but had a deep laceration to his scalp. There were marked hepatomegaly and epigastric tenderness. Haemoglobin was 94 and WBC 13.9 x 109/L. LFTs were consistent with alcoholic hepatitis. Coagulation parameters were normal. Cerebral CT was reported normal.
Hypotheses for his collapse included alcohol intoxication, sepsis, myocardial infarction, gastrointestinal bleeding, head injury, seizure, other drug use ….
Oral thiamine 100mg bd and alcohol withdrawal scale (AWS) were started, reaching a maximum 7 on the 3rd day of admission. Oral diazepam was given, totalling 20mg, 30mg and 60mg on the first 3 days. On the 4th day the patient showed flat affect, slow speech and had a gross tremor of both hands, and a wide-based ataxic gait. Mini Mental State Examination score was 24/30. The patient was disoriented in time and place with poor performance evident in short term recall, abstract thinking and construction.
The differential diagnosis of his ataxia and confusion included cerebellar disease, Wernicke’s and alcohol-related cerebrocortical damage. Review of his cerebral CT showed global atrophy, suggesting the possibility of repeated traumatic injury in the past.
2 weeks after admission, his activities of daily living had improved to the point where he was considered suitable for placement in the rehabilitation hostel level.
His younger brother, Carl Philip Emmanuel Bach, a 46 year old male on sickness benefits, was brought in by ambulance with a 3 day history of being essentially bed-bound; unable to walk, he had been crawling to the bathroom and showered sitting on the floor. He was currently drinking about 300g-400g alcohol/day, and had been admitted to hospital on several occasions for alcohol withdrawal-related seizures.
Hypotheses for his inability to walk included cerebellar disease, Wernicke’s and alcohol-and malnutrition-related muscle wasting.
On examination, he had profound truncal and gait ataxia, pronounced scanning dystharthria, and symmetrical vertical and horizontal nystagmus; dysmetria (finger-nose past-pointing), dysdiadochokinesia and heel-shin ataxia. Limb muscle power, tone and reflexes were normal but there were diminished light touch sensation in the hands, and diminished light touch and pin-prick sensation and proprioception in the feet.
Investigations: he had negative serology for HIV, and screen for a range of neuronal antibodies was negative; cerebral CT was reported as showing generalised cerebral and cerebellar atrophy. There was no enhancement of the mamillary bodies with contrast (a radiological sign of necrosis at this site in Wernicke's disease). Electromyogram was consistent with moderate-severe peripheral neuropathy.
The diagnosis of alcoholic cerebellar degeneration, with severe midline and lateral cerebellar dysfunction, was made. After 4 months in the rehabilitation ward, he remained unsafe walking even with support, and hostel accommodation was required.
Ms PDQ Bach, 52 years old, was brought in by ambulance after falling down the stairs at home. She had been drinking daily since the age of 30. She had previously worked as an auditor but had been unable to work for the previous 4 years; she had been lately prone to leaving the house for a walk with the doors and windows wide open and no-one at home.
She was conscious and oriented with a Glasgow Coma Scale score of 16. There were marked hepatomegaly and cerebellar ataxia. She was incontinent of urine and faeces. LFTs showed alcoholic hepatitis. Cervical spine and cerebral CTs were normal.
The hypotheses for her fall were similar to those for her elder brother. She too was given oral thiamine 100mg and an alcohol withdrawal scale (AWS) was commenced, The AWS peaked at 6 on the 3rd day, and a total of 50mg of diazepam was given on this day, 60mg on the fourth day and the final AWS-determined dose of diazepam at lunch time on day 5, however PRN diazepam continued.
On the 6th day, PDQ’s gait remained unsteady and shuffling and she was mildly disoriented and belligerent, with a MMSE score of 23. She did not see why she should stay in hospital, though she could not walk safely, and was still incontinent of urine.
Hypotheses for her mental state included Wernicke’s, alcohol-related cerebrocortical damage, and the effects of continuing diazepam.
On the 15th day, the patient attempted to leave the hospital, wandering, confused, disoriented, paranoid and agitated. On psychiatric assessment, she was determined to have no perceptual disturbances or evidence of paranoia, but evidence of confabulation. The Mini Mental State Examination score was 21/30 with poor registration and recall, abstract thinking, sentence repetition and design. She was treated with haloperidol 5mg orally, and risperidone to begin 0.5mg orally bd; a 24 hour attendant was arranged under 'duty of care' provisions.
Formal neuropsychiatric testing later showed impaired cognition, delayed information recall with inclusion of intrusive and incorrect information, slow psychomotor function, including slow page scanning; reduced awareness and insight; deficits in cognitive and semantic fluency, visuo-spacial and visuo-constructional skills. These were said to be all consistent with alcoholic brain damage: further the memory problems were considered consistent with Korsakoff's syndrome.
Nine weeks after admission, the patient was still awaiting suitable placement.
In each of these cases, Dr Haber suggested thiamine should ideally have been given parenterally in the emergency department, rather than orally.
Written by Richard Hallinan FAChAM based on talk and power point presentation by Prof Paul Haber on Tuesday 20th April 2010 at Concord Hospital as part of the Concord Dependency Seminar Series. http://dependencyseminars.blogspot.com/
5 December 2009
The GREAT debate - what is the best drug for dependency?
Concord Seminar Series – Tues 1st December 2009.
Collegial debate: What is the drug of first choice for opioid dependence?
In this seminar we had four cases "for the sake of argument" as to what should be the drug of first choice for opioid dependence.
Richard Hallinan first argued the case for buprenorphine.
The first point is buprenorphine's similar efficacy and cost effectiveness compared with methadone. Systematic reviews show retention in treatment was superior for flexible MMT over flexible BMT dosing but no significant difference in opiate use; overall MMT was slightly more effective and less costly than BMT (Connock et al 2007; Mattick et al 2008, Cochrane).
Lower retention may reflect an advantage of buprenorphine, the ease of reductions & withdrawal. Buprenorphine had the highest cost effectiveness for inpatient or outpatient withdrawal management of the modalities examined in the NEPOD studies (Shanahan et al 2006); and the ease of reductions/withdrawal in short term dosing 1-4 weeks is endorsed in a Cochrane review (Gowing et al 2009). Buprenorphine has great flexibility as a "gateway" treatment, whether to abstinence, naltrexone (O’Connor et al 1997; Collins et 2005; Umbricht et 1999), or MMT.
The third major point is buprenorphine's greater margin of safety than methadone, reflected in low mortality rates in BMT in France despite liberal availability and unsupervised dosing for a number of years. “Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT" (Connock et al 2007). In a 10 year longitudinal follow-up of participants in a randomized trial of MMT vs BMT there was no significant difference in mortality by treatment group (Gibson et al 2008). NSW data following up all MMT and BMT starts showed "Despite shorter retention in treatment, buprenorphine maintenance was not associated with higher risk of death." (Bell et al 2009).
Buprenorphine has fewer & less severe side effects and drug interactions compared with methadone. QT prolongation is not associated with buprenorphine, and pharmacokinetic interactions are less troublesome, partly because of the wide safety margin of buprenorphine itself. Sexual side effects appear to be lower with buprenorphine. Most importantly, sedation, especially with benzodiazepines, is less. (Lintzeris et al 2006, 2007)
A further argument in favour of buprenorphine as first line treatment is that a stepped care model starting with buprenorphine progressing to MMT has been shown to be non-inferior to standard MMT (Kakko et al 2007, 96 self-referred subjects randomised). Outcomes were virtually identical for retention in treatment and proportion of urine samples free of illicit drugs. Among completers of stepped therapy, 46% ultimately remained on buprenorphine/naloxone.
A number of RCTs show equivalence of second daily or thrice weekly dosing to daily dosing. Less frequent attendance has greater acceptability to patients, and there is reduced need for take-home or unsupervised doses, reduced risk of diversion, and potentially greater public and political acceptability of this treatment.
Finally there is the existence of a formulation of buprenorphine less attractive to injectors, buprenorphine/naloxone. “Most (68%) had tried the buprenorphine +naloxone combination IV, but 80% said they had a "bad" experience. Its street price was less than half that of buprenorphine alone.” (Alho et al 2006). “In the year after its introduction in Australia, BNX was injected less frequently and by fewer regular IDUs and clients compared with BPN” and compared with methadone. (Degenhardt et al 2009, IDRS, 2003-2007, adjusted for sales).
RH concluded: "What I am not saying: is that buprenorphine is "better". But why would you NOT choose as first line treatment a medication of similar efficacy and cost effectiveness, greater safety, better side effect profile, lower drug interactions, greater ease of reductions, and greater public acceptability than MMT, which gives equivalent results in a stepped care model to standard MMT? "
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Prof Nicholas Lintzeris next argued why sustained release oxycodone (or indeed sustained release morphine, now available in twice daily and even once daily formulations) would be the ideal drug for opioid maintenance treatment. This is admittedly hypothetical since current NSW law only allows oxycodone hydrochloride for pain indications in non-dependent patients except under specific authority from PSB.
Prof Nicholas Lintzeris gave the case for oxycodone based on:
# Pharmacological principles (sustained delivery, avoiding peaks and troughs, possibly even superior in this respect to methadone which can fluctuate widely within a 24 hour period and sometimes needs twice daily dosing to avoid emergence of withdrawal symptoms).
# Side effects (there may be less constipation and sweating than with methadone)
# Overcoming demand problems (these medications are already preferred by many, if not most, opioid dependent people, on grounds of greater predictability and safety and lower cost, compared with heroin).
# Overcoming supply problems (any doctor can feel comfortable prescribing these medications, as they already do so for pain, provided they adhere to risk management strategies; the risks and difficulties associated with long half life agonists - accumulations and overdose - do not apply).
# Stigma (methadone has a stigma which discourages many people from entering maintenance treatments).
# Do-it-yourself injectables clinic.
There is an existing, albeit limited evidence base regarding the use of slow release oral morphine to treat opioid dependence (e.g. see Mitchell, White et al 2004 - below), demonstrating the such approaches are feasible. In Austria, oral morphine is a licensed and available treatment approach for opioid dependence, and accounts for approximately a third of treatment places. An important step forward however for more widespread uptake of this approach is development of abuse deterrent preparations that reduce the risk of injecting formulations.
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Richard Hallinan then put the case for naltrexone. Naltrexone is the most direct path to abstinence, the gold standard treatment outcome. It has minimal side effects, no opioid side effects, minimal drug interactions, is non dependency forming, reduces opioid craving, and it’s easy to stop.
Naltrexone also has other therapeutic benefits including effectiveness in reducing alcohol consumption (Cochrane standard evidence), effectiveness for weight loss (especially in combination with bupropion) and effectiveness to reduce amphetamine use (Jayaram-Lindstrom et al 2008 RCT n=80, vs placebo).
Naltrexone ought to be first line treatment, however currently it is manifestly not so, neither as doctor or patient preference. Low demand and uptake reflects low patient enthusiasm, poor retention, and in Australia the cost, as the treatment is unsubsidised. There are also difficulties of induction, including the high cost of rapid opioid "detoxification" as the preliminary step.
There is a lack of RCT evidence supporting oral naltrexone: poor treatment retention, and modest heroin use reduction compared with placebo, which was non-significant with adequate concealment. (Minozzi et al 2006, Cochrane review). There was also greatly elevated overdose risk due to poor treatment retention. “The relative risk of death for oral naltrexone subjects was 7.4 times (high-risk period, p < 0.0001) or 2.8 times (low-risk period, p = 0.055) that of methadone subjects.” (Gibson and Degenhardt 2007, see also Digiusto et al 2004, NEPOD).
Naltrexone is safe and effective if people take it. As the problem is compliance with oral naltrexone, naltrexone sustained delivery formulations should be the answer. Unfortunately, large scale use of naltrexone implants began in Australia before preclinical, phase 1, 2 or 3 studies were carried out. Various formulations and devices have been offered in different places, and at different times, with some doubts about uniformity of manufacture and good manufacturing practice accreditation over the years.
Even nearly a decade later, the published literature leaves the critical reader in doubt about the rate of serious adverse effects, the efficacy of implants (duration of adequate blood levels and inter-individual variability in blood levels), the risk of problematic use of other substances, and long term outcomes.
Retrospective and naturalistic studies for efficacy and safety, however, suggest probably higher safety from implant formulations compared with oral naltrexone, and at least comparable safety (in terms of mortality) compared with MMT and BMT.
In Western Australia, naltrexone implant treatment was associated with reduced opiate overdoses compared with pretreatment, but increased sedative and other drug overdoses and other drug related hospital admissions (Hulse et al. 2005, Ngo et al. 2008). In Queensland, a retrospective study from a single treatment centre found lower crude mortality but no significant difference in standardized mortality rate for naltrexone implant compared to BMT (Reece 2007). Similarly Tait et al. (2007) found age standardized mortality rate ratio for naltrexone implant vs MMT to be 0.65 (95% CI = 0.12–1.2 NS).
There have been two RCTs of the “GoMedical” naltrexone implant. Kunøe et al 2009 (n=56, 180 days) found lower heroin use, fewer days’ use compared with “normal after care”. Hulse et al 2009 (vs oral Ntx, n=70, 180 days) found lower self reported opiate use, but no difference in urine test confirmed heroin use; other drug use, especially non-heroin opioid use, was poorly assessed. The average duration of adequate blood naltrexone level was substantially revised downwards, compared with previous studies. The good news was that in neither study were there any deaths in patients who received implants.
RH concluded: "What I am not saying is that naltrexone is 'better'. But everyone deserves a chance at abstinence before being committed to agonist therapy, which leaves patients physically dependent on opioids with their considerable side effects, as well as being subjected to intrusions and restrictions on their lives, which may be for many years with no good evidence for how to end the treatment. The future of naltrexone treatment for opioid dependence must be sustained release naltrexone preparations."
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Andrew Byrne, Redfern Surgery.
Methadone is the drug of choice for opioid dependence. Forty years of research prove that this therapy is effective in retaining patients in treatment, reducing illicit drugs use, lowering viral transmission and eliminating almost 80% of overdose deaths. None of these benefits has been shown to the same degree for buprenorphine and thus it should not be recommended as first line drug unless there are contraindications for methadone. Further benefits for those taking methadone is that it is safe in pregnancy and lactation while it is also more widely available both in Australia and around the world.
A possible increase in the overdose rate in the first two weeks of treatment is balanced by high numbers of drop-outs in the first two weeks of buprenorphine treatment. A recent large study in Norway showed two deaths in the first month of treatment out of over 3000 episodes in a seven year period.
However, patients make the choice about which drug much more often than doctors do (see below).
Cost effectiveness is far more positive with methadone, being an inexpensive non-patented drug. Common side effects are limited to constipation and sweating. More serious side effects can be limited by dose adjustments and hormone replacement when testosterone levels are suppressed. QT prolongation is common but appears to be of no clinical significance in isolation. Torsade de pointes tachycardia has only been associated with multiple risk factors some of which coincide with long-term survivors of opioid use, prescribed medications, alcohol and illicit drug use. Methadone has not been demonstrated to cause torsade and it is possible that higher doses make this less likely to occur. It is generally agreed that as with other drugs having a dose response, there should be no arbitrary limit on methadone dose levels.
Some references were detailed for the Concord audience.
RCT buprenorphine/methadone.
Ling W, Charuvastra C et al.
Mattick RP, Ali R, White JM et al.
Kristensen O, Espegren O et al.
Kakko J, Grönbladh L, Svanborg KD et al.
Pinto H, Rumball D et al.
Kamien JB, Branstetter SA, Amass L.
Petitjean S, Stohler R, Déglon JJ et al.
Cochrane Database of Systematic Reviews
Reasons for choosing MMT.
Cost (cheapest drug around)
Safe in pregnancy
Available most widely (Aussie pts travel!)
Highest retention rate
Lowest illicit drug use rates
Safety when used under supervision
Original and best known.
How many patients have already tried both methadone and buprenorphine? It seems that the majority of patients attending for opioid dependency treatment are now aware of both methadone and buprenorphine and most have a clear idea which is best for them. This is due to personal trial and error or else street talk of the properties of both. But is this all hypothetical? Doctors are in fact only rarely in a position to decide/advise between methadone and buprenorphine.
English GP study
A pilot study for a randomized controlled and patient preference trial of buprenorphine versus methadone maintenance treatment in the management of opiate dependent patients. Dr Pinto in England was trying to prove that buprenorphine had benefits worth including on the NHS formulary for their area. Out of 42 subjects recruited, none agreed to be randomized. The reason was that all patients had a clear idea which drug they wanted and refused to consider alternatives in this trial setting.
Pinto H, Rumball D, et al. Journal of Substance Use 2008 13;2:73-82
World’s largest study on OTP.
Burns L, Randall D, Hall WD, Law M, Butler T, Bell J, Degenhardt L. Opioid agonist pharmacotherapy in New South Wales from 1985 to 2006: patient characteristics and patterns and predictors of treatment retention. Addiction 2009 104;8:1363-1372
Burns et al. abstract quotes:
“the hazard of leaving treatment was 1.9 times for those on buprenorphine relative to those on methadone”
“This study has provided population-level evidence to suggest that retention in methadone and buprenorphine differ in routine clinical practice.” (retention in methadone was much better).
Things go better with methadone!
Much lower diversion rates (anecdotally)
No substantial problems with contaminated drug being injected (unlike buprenorphine).
Less “revolving door” syndrome as with buprenorphine (see Burns’ latest study).
Best drug for addiction Rx.
Do you want your patient to have the best chances of getting their lives together, staying in treatment and avoiding illicit drugs?
Of course you do!
Then you should recommend methadone as a first option when there is a choice.
Is this debate “for real”?
Would we be having this debate about antibiotics, antidepressants or hypertension drugs?
Of course not!
**Treatment matching** is the way to go. [Which brings us to the case studies presented in the second half (see below)]
Dependency medicine has a way to go, too!
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Post Script
RH introduced several intentional errors/dubious claims in his presentations, some of which were identified by participants, and others swallowed whole, perhaps owing to the poker faced delivery.
There is no good evidence that naltrexone reduces opioid craving.
Evidence that sexual side effects are lower with buprenorphine is weak, and there is no research for women.
Second daily or thrice weekly buprenorphine dosing in clinical practice seems to suits only a minority.
Naltrexone alone, without bupropion, has small effectiveness for weight loss.
RCT evidence does not support claims for greater safety for buprenorphine (but as NL pointed out, safety for 3rd parties, especially children, is certainly greater for buprenorphine).
There is no evidence that reductions over a longer period are easier for buprenorphine than methadone, and 2 studies sometimes cited to support the claim short term ease of buprenorphine reductions compared with methadone compared a buprenorphine + carbamazepine regime to an methadone + carbamazepine regime. Carbamazepine is a powerful inducer of the metabolism of methadone. (Seifert et al 2002, 2005)
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Concord Dependency Seminar November 2009, Treatment Matching - Case Studies
Kyle, a 19 yo heroin user, has been smoking heroin since age 16, daily for the last year, and recently he started injecting it. He used MDMA on weekends from age 16, seldom drinks alcohol or smokes THC, but smokes cigarettes. He has previously "dried out" several times using his mother’s Serepax, but stayed clean for only 3-10 days. He is a student at uni doing arts/law, and lives with his parents. He has maxed out credit card, has stolen money from his parents, used up all a private inheritance from his grandfather who died 3 years ago ($40,000).
Kyle feels he has lost control. He badly needs money, and feels he may have to work as a prostitute. He doesn’t want anyone to know he is using heroin, and is terrified his step-father (a public prosecutor) will find out. He can’t go away or do a rehab for this reason, and anyway he is in the middle of term with exams in 6 weeks. He asks for medications so he won’t have to use heroin.
What treatment is first choice for Kyle?
Comments: a show of hands gave majority support for buprenorphine for this patient, owing to his current predicament, and the short duration of his opioid dependence. He might use buprenorphine for withdrawal management and go onto maintenance if needed. Ross Colquhoun (who will present his experience with naltrexone implants in the Feb 2010 Concord seminar) felt this patient would do very well with naltrexone implant, but this would be too disruptive currently and he should be stabilised on buprenorphine first. Cost would probably also be a major problem.
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Robbie is 41 yo, and has been a disability pensioner for 15 years for "mental health problems", including psychosis. He has been an involuntary inpatient for extended periods, including 6 months last year, and his community treatment order has ended. He is no longer getting depot flupenthixol. Two recent hospital admissions under the mental heath act were for aggression/violence. He comes asking for treatment because he has been hanging out, says he has been using $200/day of heroin (he says he has a neighbour who is a dealer). He says he was on MMT once before for 18 months but didn’t like it. Sometime he does inject BM methadone.
On examination he is in classic opioid withdrawal, and has plenty of old scars and recent tracks.
A call to the local mental health service confirms his psychotic episodes have often been precipitated by alcohol or, apparently, amphetamines. He also uses benzodiazepines and cannabis, according to previous history and urine toxicology.
What treatment is first choice for Robbie?
Comments: a show of hands gave majority support for methadone for this patient, owing to his psychotic illness and the antipsychotic properties of methadone. Retention in treatment might be an issue with buprenorphine given his previous poor compliance with antipsychotics. However, doubt was cast on the history of heroin use, as it seems unlikely a long standing disability pensioner for "mental health problems" would have the capacity and resources to afford $200/day. Induction onto methadone would have to be very cautious. It was noted that amphetamine intoxication could potentially be confused with opioid withdrawal. Naltrexone treatment was generally considered inappropriate.
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Emma is 36, and a business analyst working for a merchant bank. She is single, works hard and plays hard, and loves having the freedom to party. But partying has got a bit out of control. She admits to near daily drinking (60-90g/day for several years), & occasional use of cocaine on the weekends. There is also frequent use of over-the-counter and prescribed codeine (40-120mg/day) and oral amphetamines as a "pick me up" during the week.
3 months ago Emma was introduced to heroin. She has recently injected it a few times and now is afraid she might be getting a habit. She wakes up craving heroin, can’t get it off her mind, and uses codeine to get through the day. She finds heroin really helps with her severe period pains and wonders about getting a hysterectomy. The heroin use worries her because she doesn’t want to be addicted. She despises junkies and is appalled by the idea of methadone.
What treatment is first choice for Emma?
Comments: the majority view was that alcohol was her primary problem, and her other drug problems (use of codeine and amphetamines for hangover) might be more easily controlled if she could achieve alcohol abstinence. An inpatient opioid/alcohol withdrawal management and a period of residential rehabilitation, or intensive outpatient counseling supported by alcohol pharmacotherapy would be the best option if she were prepared to try it.
However, if opioid maintenance was needed, a show of hands gave majority support for buprenorphine for this patient, owing to her resistance to methadone and the possibility that alcohol use might be less problematic if she were on a partial agonist. However the gynaecological problems need assessment and management, and her chronic pain might make a full opioid agonist necessary. NL argued that this is exactly the sort of patient who would do well with supervised dosing of a sustained release opioid such as oxycodone, which might be justified for her chronic pain, and which she would probably find more acceptable than methadone or buprenorphine. Ross Colquhoun felt this patient would do very well with naltrexone implant, which would also help with her alcohol problem.
Ref 1.
Mitchell TB, White JM, Somogyi AA, Bochner F. Slow-release oral morphine versus methadone: a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence. Addiction. 2004; 99:940-5
Collegial debate: What is the drug of first choice for opioid dependence?
In this seminar we had four cases "for the sake of argument" as to what should be the drug of first choice for opioid dependence.
Richard Hallinan first argued the case for buprenorphine.
The first point is buprenorphine's similar efficacy and cost effectiveness compared with methadone. Systematic reviews show retention in treatment was superior for flexible MMT over flexible BMT dosing but no significant difference in opiate use; overall MMT was slightly more effective and less costly than BMT (Connock et al 2007; Mattick et al 2008, Cochrane).
Lower retention may reflect an advantage of buprenorphine, the ease of reductions & withdrawal. Buprenorphine had the highest cost effectiveness for inpatient or outpatient withdrawal management of the modalities examined in the NEPOD studies (Shanahan et al 2006); and the ease of reductions/withdrawal in short term dosing 1-4 weeks is endorsed in a Cochrane review (Gowing et al 2009). Buprenorphine has great flexibility as a "gateway" treatment, whether to abstinence, naltrexone (O’Connor et al 1997; Collins et 2005; Umbricht et 1999), or MMT.
The third major point is buprenorphine's greater margin of safety than methadone, reflected in low mortality rates in BMT in France despite liberal availability and unsupervised dosing for a number of years. “Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT" (Connock et al 2007). In a 10 year longitudinal follow-up of participants in a randomized trial of MMT vs BMT there was no significant difference in mortality by treatment group (Gibson et al 2008). NSW data following up all MMT and BMT starts showed "Despite shorter retention in treatment, buprenorphine maintenance was not associated with higher risk of death." (Bell et al 2009).
Buprenorphine has fewer & less severe side effects and drug interactions compared with methadone. QT prolongation is not associated with buprenorphine, and pharmacokinetic interactions are less troublesome, partly because of the wide safety margin of buprenorphine itself. Sexual side effects appear to be lower with buprenorphine. Most importantly, sedation, especially with benzodiazepines, is less. (Lintzeris et al 2006, 2007)
A further argument in favour of buprenorphine as first line treatment is that a stepped care model starting with buprenorphine progressing to MMT has been shown to be non-inferior to standard MMT (Kakko et al 2007, 96 self-referred subjects randomised). Outcomes were virtually identical for retention in treatment and proportion of urine samples free of illicit drugs. Among completers of stepped therapy, 46% ultimately remained on buprenorphine/naloxone.
A number of RCTs show equivalence of second daily or thrice weekly dosing to daily dosing. Less frequent attendance has greater acceptability to patients, and there is reduced need for take-home or unsupervised doses, reduced risk of diversion, and potentially greater public and political acceptability of this treatment.
Finally there is the existence of a formulation of buprenorphine less attractive to injectors, buprenorphine/naloxone. “Most (68%) had tried the buprenorphine +naloxone combination IV, but 80% said they had a "bad" experience. Its street price was less than half that of buprenorphine alone.” (Alho et al 2006). “In the year after its introduction in Australia, BNX was injected less frequently and by fewer regular IDUs and clients compared with BPN” and compared with methadone. (Degenhardt et al 2009, IDRS, 2003-2007, adjusted for sales).
RH concluded: "What I am not saying: is that buprenorphine is "better". But why would you NOT choose as first line treatment a medication of similar efficacy and cost effectiveness, greater safety, better side effect profile, lower drug interactions, greater ease of reductions, and greater public acceptability than MMT, which gives equivalent results in a stepped care model to standard MMT? "
_________________________________________________
Prof Nicholas Lintzeris next argued why sustained release oxycodone (or indeed sustained release morphine, now available in twice daily and even once daily formulations) would be the ideal drug for opioid maintenance treatment. This is admittedly hypothetical since current NSW law only allows oxycodone hydrochloride for pain indications in non-dependent patients except under specific authority from PSB.
Prof Nicholas Lintzeris gave the case for oxycodone based on:
# Pharmacological principles (sustained delivery, avoiding peaks and troughs, possibly even superior in this respect to methadone which can fluctuate widely within a 24 hour period and sometimes needs twice daily dosing to avoid emergence of withdrawal symptoms).
# Side effects (there may be less constipation and sweating than with methadone)
# Overcoming demand problems (these medications are already preferred by many, if not most, opioid dependent people, on grounds of greater predictability and safety and lower cost, compared with heroin).
# Overcoming supply problems (any doctor can feel comfortable prescribing these medications, as they already do so for pain, provided they adhere to risk management strategies; the risks and difficulties associated with long half life agonists - accumulations and overdose - do not apply).
# Stigma (methadone has a stigma which discourages many people from entering maintenance treatments).
# Do-it-yourself injectables clinic.
There is an existing, albeit limited evidence base regarding the use of slow release oral morphine to treat opioid dependence (e.g. see Mitchell, White et al 2004 - below), demonstrating the such approaches are feasible. In Austria, oral morphine is a licensed and available treatment approach for opioid dependence, and accounts for approximately a third of treatment places. An important step forward however for more widespread uptake of this approach is development of abuse deterrent preparations that reduce the risk of injecting formulations.
_____________________________________________________________
Richard Hallinan then put the case for naltrexone. Naltrexone is the most direct path to abstinence, the gold standard treatment outcome. It has minimal side effects, no opioid side effects, minimal drug interactions, is non dependency forming, reduces opioid craving, and it’s easy to stop.
Naltrexone also has other therapeutic benefits including effectiveness in reducing alcohol consumption (Cochrane standard evidence), effectiveness for weight loss (especially in combination with bupropion) and effectiveness to reduce amphetamine use (Jayaram-Lindstrom et al 2008 RCT n=80, vs placebo).
Naltrexone ought to be first line treatment, however currently it is manifestly not so, neither as doctor or patient preference. Low demand and uptake reflects low patient enthusiasm, poor retention, and in Australia the cost, as the treatment is unsubsidised. There are also difficulties of induction, including the high cost of rapid opioid "detoxification" as the preliminary step.
There is a lack of RCT evidence supporting oral naltrexone: poor treatment retention, and modest heroin use reduction compared with placebo, which was non-significant with adequate concealment. (Minozzi et al 2006, Cochrane review). There was also greatly elevated overdose risk due to poor treatment retention. “The relative risk of death for oral naltrexone subjects was 7.4 times (high-risk period, p < 0.0001) or 2.8 times (low-risk period, p = 0.055) that of methadone subjects.” (Gibson and Degenhardt 2007, see also Digiusto et al 2004, NEPOD).
Naltrexone is safe and effective if people take it. As the problem is compliance with oral naltrexone, naltrexone sustained delivery formulations should be the answer. Unfortunately, large scale use of naltrexone implants began in Australia before preclinical, phase 1, 2 or 3 studies were carried out. Various formulations and devices have been offered in different places, and at different times, with some doubts about uniformity of manufacture and good manufacturing practice accreditation over the years.
Even nearly a decade later, the published literature leaves the critical reader in doubt about the rate of serious adverse effects, the efficacy of implants (duration of adequate blood levels and inter-individual variability in blood levels), the risk of problematic use of other substances, and long term outcomes.
Retrospective and naturalistic studies for efficacy and safety, however, suggest probably higher safety from implant formulations compared with oral naltrexone, and at least comparable safety (in terms of mortality) compared with MMT and BMT.
In Western Australia, naltrexone implant treatment was associated with reduced opiate overdoses compared with pretreatment, but increased sedative and other drug overdoses and other drug related hospital admissions (Hulse et al. 2005, Ngo et al. 2008). In Queensland, a retrospective study from a single treatment centre found lower crude mortality but no significant difference in standardized mortality rate for naltrexone implant compared to BMT (Reece 2007). Similarly Tait et al. (2007) found age standardized mortality rate ratio for naltrexone implant vs MMT to be 0.65 (95% CI = 0.12–1.2 NS).
There have been two RCTs of the “GoMedical” naltrexone implant. Kunøe et al 2009 (n=56, 180 days) found lower heroin use, fewer days’ use compared with “normal after care”. Hulse et al 2009 (vs oral Ntx, n=70, 180 days) found lower self reported opiate use, but no difference in urine test confirmed heroin use; other drug use, especially non-heroin opioid use, was poorly assessed. The average duration of adequate blood naltrexone level was substantially revised downwards, compared with previous studies. The good news was that in neither study were there any deaths in patients who received implants.
RH concluded: "What I am not saying is that naltrexone is 'better'. But everyone deserves a chance at abstinence before being committed to agonist therapy, which leaves patients physically dependent on opioids with their considerable side effects, as well as being subjected to intrusions and restrictions on their lives, which may be for many years with no good evidence for how to end the treatment. The future of naltrexone treatment for opioid dependence must be sustained release naltrexone preparations."
____________________________________________________
Andrew Byrne, Redfern Surgery.
Methadone is the drug of choice for opioid dependence. Forty years of research prove that this therapy is effective in retaining patients in treatment, reducing illicit drugs use, lowering viral transmission and eliminating almost 80% of overdose deaths. None of these benefits has been shown to the same degree for buprenorphine and thus it should not be recommended as first line drug unless there are contraindications for methadone. Further benefits for those taking methadone is that it is safe in pregnancy and lactation while it is also more widely available both in Australia and around the world.
A possible increase in the overdose rate in the first two weeks of treatment is balanced by high numbers of drop-outs in the first two weeks of buprenorphine treatment. A recent large study in Norway showed two deaths in the first month of treatment out of over 3000 episodes in a seven year period.
However, patients make the choice about which drug much more often than doctors do (see below).
Cost effectiveness is far more positive with methadone, being an inexpensive non-patented drug. Common side effects are limited to constipation and sweating. More serious side effects can be limited by dose adjustments and hormone replacement when testosterone levels are suppressed. QT prolongation is common but appears to be of no clinical significance in isolation. Torsade de pointes tachycardia has only been associated with multiple risk factors some of which coincide with long-term survivors of opioid use, prescribed medications, alcohol and illicit drug use. Methadone has not been demonstrated to cause torsade and it is possible that higher doses make this less likely to occur. It is generally agreed that as with other drugs having a dose response, there should be no arbitrary limit on methadone dose levels.
Some references were detailed for the Concord audience.
RCT buprenorphine/methadone.
Ling W, Charuvastra C et al.
Mattick RP, Ali R, White JM et al.
Kristensen O, Espegren O et al.
Kakko J, Grönbladh L, Svanborg KD et al.
Pinto H, Rumball D et al.
Kamien JB, Branstetter SA, Amass L.
Petitjean S, Stohler R, Déglon JJ et al.
Cochrane Database of Systematic Reviews
Reasons for choosing MMT.
Cost (cheapest drug around)
Safe in pregnancy
Available most widely (Aussie pts travel!)
Highest retention rate
Lowest illicit drug use rates
Safety when used under supervision
Original and best known.
How many patients have already tried both methadone and buprenorphine? It seems that the majority of patients attending for opioid dependency treatment are now aware of both methadone and buprenorphine and most have a clear idea which is best for them. This is due to personal trial and error or else street talk of the properties of both. But is this all hypothetical? Doctors are in fact only rarely in a position to decide/advise between methadone and buprenorphine.
English GP study
A pilot study for a randomized controlled and patient preference trial of buprenorphine versus methadone maintenance treatment in the management of opiate dependent patients. Dr Pinto in England was trying to prove that buprenorphine had benefits worth including on the NHS formulary for their area. Out of 42 subjects recruited, none agreed to be randomized. The reason was that all patients had a clear idea which drug they wanted and refused to consider alternatives in this trial setting.
Pinto H, Rumball D, et al. Journal of Substance Use 2008 13;2:73-82
World’s largest study on OTP.
Burns L, Randall D, Hall WD, Law M, Butler T, Bell J, Degenhardt L. Opioid agonist pharmacotherapy in New South Wales from 1985 to 2006: patient characteristics and patterns and predictors of treatment retention. Addiction 2009 104;8:1363-1372
Burns et al. abstract quotes:
“the hazard of leaving treatment was 1.9 times for those on buprenorphine relative to those on methadone”
“This study has provided population-level evidence to suggest that retention in methadone and buprenorphine differ in routine clinical practice.” (retention in methadone was much better).
Things go better with methadone!
Much lower diversion rates (anecdotally)
No substantial problems with contaminated drug being injected (unlike buprenorphine).
Less “revolving door” syndrome as with buprenorphine (see Burns’ latest study).
Best drug for addiction Rx.
Do you want your patient to have the best chances of getting their lives together, staying in treatment and avoiding illicit drugs?
Of course you do!
Then you should recommend methadone as a first option when there is a choice.
Is this debate “for real”?
Would we be having this debate about antibiotics, antidepressants or hypertension drugs?
Of course not!
**Treatment matching** is the way to go. [Which brings us to the case studies presented in the second half (see below)]
Dependency medicine has a way to go, too!
_______________________________________________________
Post Script
RH introduced several intentional errors/dubious claims in his presentations, some of which were identified by participants, and others swallowed whole, perhaps owing to the poker faced delivery.
There is no good evidence that naltrexone reduces opioid craving.
Evidence that sexual side effects are lower with buprenorphine is weak, and there is no research for women.
Second daily or thrice weekly buprenorphine dosing in clinical practice seems to suits only a minority.
Naltrexone alone, without bupropion, has small effectiveness for weight loss.
RCT evidence does not support claims for greater safety for buprenorphine (but as NL pointed out, safety for 3rd parties, especially children, is certainly greater for buprenorphine).
There is no evidence that reductions over a longer period are easier for buprenorphine than methadone, and 2 studies sometimes cited to support the claim short term ease of buprenorphine reductions compared with methadone compared a buprenorphine + carbamazepine regime to an methadone + carbamazepine regime. Carbamazepine is a powerful inducer of the metabolism of methadone. (Seifert et al 2002, 2005)
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Concord Dependency Seminar November 2009, Treatment Matching - Case Studies
Kyle, a 19 yo heroin user, has been smoking heroin since age 16, daily for the last year, and recently he started injecting it. He used MDMA on weekends from age 16, seldom drinks alcohol or smokes THC, but smokes cigarettes. He has previously "dried out" several times using his mother’s Serepax, but stayed clean for only 3-10 days. He is a student at uni doing arts/law, and lives with his parents. He has maxed out credit card, has stolen money from his parents, used up all a private inheritance from his grandfather who died 3 years ago ($40,000).
Kyle feels he has lost control. He badly needs money, and feels he may have to work as a prostitute. He doesn’t want anyone to know he is using heroin, and is terrified his step-father (a public prosecutor) will find out. He can’t go away or do a rehab for this reason, and anyway he is in the middle of term with exams in 6 weeks. He asks for medications so he won’t have to use heroin.
What treatment is first choice for Kyle?
Comments: a show of hands gave majority support for buprenorphine for this patient, owing to his current predicament, and the short duration of his opioid dependence. He might use buprenorphine for withdrawal management and go onto maintenance if needed. Ross Colquhoun (who will present his experience with naltrexone implants in the Feb 2010 Concord seminar) felt this patient would do very well with naltrexone implant, but this would be too disruptive currently and he should be stabilised on buprenorphine first. Cost would probably also be a major problem.
_______________________________________________
Robbie is 41 yo, and has been a disability pensioner for 15 years for "mental health problems", including psychosis. He has been an involuntary inpatient for extended periods, including 6 months last year, and his community treatment order has ended. He is no longer getting depot flupenthixol. Two recent hospital admissions under the mental heath act were for aggression/violence. He comes asking for treatment because he has been hanging out, says he has been using $200/day of heroin (he says he has a neighbour who is a dealer). He says he was on MMT once before for 18 months but didn’t like it. Sometime he does inject BM methadone.
On examination he is in classic opioid withdrawal, and has plenty of old scars and recent tracks.
A call to the local mental health service confirms his psychotic episodes have often been precipitated by alcohol or, apparently, amphetamines. He also uses benzodiazepines and cannabis, according to previous history and urine toxicology.
What treatment is first choice for Robbie?
Comments: a show of hands gave majority support for methadone for this patient, owing to his psychotic illness and the antipsychotic properties of methadone. Retention in treatment might be an issue with buprenorphine given his previous poor compliance with antipsychotics. However, doubt was cast on the history of heroin use, as it seems unlikely a long standing disability pensioner for "mental health problems" would have the capacity and resources to afford $200/day. Induction onto methadone would have to be very cautious. It was noted that amphetamine intoxication could potentially be confused with opioid withdrawal. Naltrexone treatment was generally considered inappropriate.
_______________________________________________
Emma is 36, and a business analyst working for a merchant bank. She is single, works hard and plays hard, and loves having the freedom to party. But partying has got a bit out of control. She admits to near daily drinking (60-90g/day for several years), & occasional use of cocaine on the weekends. There is also frequent use of over-the-counter and prescribed codeine (40-120mg/day) and oral amphetamines as a "pick me up" during the week.
3 months ago Emma was introduced to heroin. She has recently injected it a few times and now is afraid she might be getting a habit. She wakes up craving heroin, can’t get it off her mind, and uses codeine to get through the day. She finds heroin really helps with her severe period pains and wonders about getting a hysterectomy. The heroin use worries her because she doesn’t want to be addicted. She despises junkies and is appalled by the idea of methadone.
What treatment is first choice for Emma?
Comments: the majority view was that alcohol was her primary problem, and her other drug problems (use of codeine and amphetamines for hangover) might be more easily controlled if she could achieve alcohol abstinence. An inpatient opioid/alcohol withdrawal management and a period of residential rehabilitation, or intensive outpatient counseling supported by alcohol pharmacotherapy would be the best option if she were prepared to try it.
However, if opioid maintenance was needed, a show of hands gave majority support for buprenorphine for this patient, owing to her resistance to methadone and the possibility that alcohol use might be less problematic if she were on a partial agonist. However the gynaecological problems need assessment and management, and her chronic pain might make a full opioid agonist necessary. NL argued that this is exactly the sort of patient who would do well with supervised dosing of a sustained release opioid such as oxycodone, which might be justified for her chronic pain, and which she would probably find more acceptable than methadone or buprenorphine. Ross Colquhoun felt this patient would do very well with naltrexone implant, which would also help with her alcohol problem.
Ref 1.
Mitchell TB, White JM, Somogyi AA, Bochner F. Slow-release oral morphine versus methadone: a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence. Addiction. 2004; 99:940-5
8 August 2009
Alcohol dependence - an update for medical interventions.
Concord Seminar Tuesday 4th August 2009.
Mechanisms and Treatment of Alcohol Dependence and its Sequelae: a 2009 Update
Dr Saunders used a single, complex case of alcohol dependence to introduce an overview of neurobiological mechanisms underlying the development of dependence; and a case of fetal alcohol syndrome, as an example of alcohol related neurodegeneration.
Patient K was a woman in her early 40s who had lost a promising professional career and marriage in her late 20s after a severe neurological insult left her with cognitive impairment, gait disturbance and dysarthria. Five years later she had married again and entered into a new phase of life, but gradually developed alcohol dependence with regular consumption of 120-180g/day. Among risk factors were a family history (father) of alcoholism, and the trauma and loss resulting from her disability and possibly also the brain injury itself. Treatment followed a not unusual course of withdrawal management followed by periods of abstinence supported by acamprosate and/or naltrexone, each time with subsequent relapse.
Twin studies show about 50% of population variance of alcoholism to be genetic; there is a tendency to father-son and mother-daughter vectors. Cohort longitudinal studies point to developmental factors especially childhood abuse, be it physical, sexual, or repeated mental abuse, along with other trauma, for example PTSD. At a sociological / anthropological level, cultural, socioeconomic and regulatory factors are also important.
What are the mechanisms of dependence? While workers in the field of addiction are becoming fairly familiar with the idea of meso-limbic reward pathways, our speaker gave us a more comprehensive understanding of the neurobiological mechanisms of dependence by including also mesolimbic stress, and frontal inhibitory, control systems.
Among the neuronal reward circuits, dopaminergic pathways are especially important for psychostimulants and nicotine, and opioid pathways for alcohol and opioids. When such substances are repeatedly or continuously used, the natural activity of these systems is suppressed. A negative mood and motivational state develops: more and more of the substance is required merely to maintain the normal state, while other normally "rewarding" activities become blunted. The substance use can be said to have “high-jacked” the reward system.
At the same time, with repeated substance use the balance is re-set between brain stress and anti-stress systems, through stimulation of pathways involving the excitatory neurotransmitter glutamate and CRF (corticotrophin-releasing factor) and suppression of GABA and ‘Neuropeptide Y’ circuits. The stress systems become “supercharged” to respond to exposure to psychoactive substances and cues or trigger for the substance use.
Finally, with repeated substance use there is progressive impairment of pre-frontal-mesolimbic inhibitory pathways, with impairment of executive functioning, decision-making and insight.
In combination, suppression of reward systems, their "high-jacking” by substance use, and “supercharging” of the stress systems to respond to psychoactive substances and their associated cues, generate a powerful “internal driving force” which is little influenced by voluntary control, because of impaired frontal inhibitory systems.
At this Concord Seminar, when an audience member asked about the situational and emotional triggers for alcohol use in patient K, Dr Saunders responded: "It doesn't matter what the triggers are, she is dependent. There is an overwhelming, tsunami-like force driving it."
Pharmacotherapies for alcohol dependence, included much the same list as when Dr Saunders last spoke to us in 2005, though the evidence base has developed since then.
Naltrexone (blocks opioid pathways for alcohol reinforcement/reward; see below)
Acamprosate (restores balance to GABAergic/glutaminergic stress responses; see below)
Topiramate (similarly, restoring balance to GABAergic/glutaminergic pathways in the corticomesolimbic system; several randomised trials from USA, and Finland)
Disulfiram (aversive agent, unpleasant reaction on alcohol ingestion; see below)
Ondansetron (selective 5-HT(3) (serotonin) antagonist [‘Zofran’] may be effective for patients with early-onset alcoholism, associated with greater serotonergic abnormality & greater mood disturbance, including depression, anxiety, hostility and antisocial behaviors)
Baclofen (GABA-B receptor agonist, reducing craving and alcohol intake in small trials)
Buspirone (for alcohol dependence and comorbid social anxiety)
SSRIs (for underlying or residual depression, and to be avoided in young alcoholic men with depression/suicidality, in whom they may make matters worse – the reason for this is not entirely clear, but see ondansetron above)
While a Cochrane review (Srisurapanont et al, 2005) for naltrexone gives clear evidence that relapse into alcohol dependence is reduced by some 36%, the Cochrane review of acamprosate has not yet reported, and there have been negative findings from recent US and Australian studies. There have been two important studies of combined naltrexone and acamprosate for alcohol dependence, with some evidence of benefit from the combination in Kiefer et al (2003) but little at all for acamprosate from the COMBINE Study (eg Anton et al 2006; Donovan et al 2008). There is also good evidence for improved outcomes for disulfiram, provided it is supervised.
With huge variability in findings from different studies, especially for acamprosate, Dr Saunders notes that exploring the heterogeneity of these studies may be a key for furthering our understanding and planning further research. Much may be lost by the reductionism of meta-analysis. Meanwhile, naltrexone tends to be his first line choice for alcohol dependence.
Some basic contrasts between the use of naltrexone and acamprosate are listed here.
Initiation: for naltrexone, when abstinent or when drinking; for acamprosate only when abstinent.
Onset of action: for naltrexone within 24 hours; for acamprosate one week
Pattern of drinking: for naltrexone, alcohol dependence with binge pattern; for acamprosate, alcohol dependence with regular daily drinking
Triggers to drink: for naltrexone, smell, taste, initial consumption of alcohol; for acamprosate, geographical, interpersonal and emotional triggers
Sub-type of dependence: for naltrexone, early onset & strong family history; for acamprosate, later onset.
Genetic markers: for naltrexone, having opioid receptor gene (OPMR1- Asp40 allele)
_______________________________
We were then introduced to a difficult clinical situation. An addiction specialist noticed by chance, while treating a pregnant alcoholic woman abstinent in early recovery, that a previous child had previously unrecognised fetal alcohol syndrome. Ethical issues about contacting that child’s doctor, or community services, the potentially devastating impact of informing this woman at such a time and almost certainly precipitating relapse and worse outcomes led to lively discussion. Happily in this case the fine line was successfully trod.
Fetal Alcohol Syndrome is at the most severe end of the range of Fetal Alcohol Disorder Spectrum (FASD). The features are
1. maldevelopment of the mid face, including a small flattened nose, wide-set eyes, epicanthic folds, a thin upper lip, and absent philtrum
2. microcephaly, mental retardation (average IQ 70) and behavioural abnormalities
3. congenital cardiac abnormalities
Learning difficulties become apparent in childhood, and there is no improvement in IQ over time. There are social interaction deficits, but more typically the children are over-friendly to peers and adults, and so-called moral deficits – high prevalence of promiscuity, sexually transmitted diseases in teen years - may be attributable to these factors.
Management consists of teaching adaptive living skills, (such as to be appropriately guarded with strangers and certain family members), educational placement, speech and language services, occupational therapy and vocational guidance, and advocacy as needed.
This brought us to the matter of alcohol and neurodegeneration, especially in young people. We are reminded that brain development continues until at least the age of 21. Particularly that during this time, but also afterwards, neurones and their connections are in a state of dynamic flux, of which ongoing neurogenesis is an essential part.
In experimental animals, with increasing alcohol exposure there is increased differentiation of neural stem cells to oligodendrocytes and astrocytes and reduced differentiation to neurones, with blunting of dendrites, and inhibition of neurogenesis as a primary mechanism of neurodegeneration. In Fetal Alcohol Syndrome there is not only major structural damage in the 1st trimester but a quantitative decline in the number of neurones in the 3rd trimester through inhibition of neurogenesis (in which tobacco smoking, diet and vitamin deficiencies probably also play a role).
For further reading, we recommend Bankole Johnson's review:
Johnson BA. Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings.Biochem Pharmacol. 2008 Jan 1;75(1):34-56. Full text available free at http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17880925
Also, Dr Saunders won't mind us giving a plug for a new "concise and practical guide for students and practitioners of medicine and other health professions who come into contact with people with substance use disorders." Addiction Medicine. Editors Noeline Latt, Katherine Conigrave, Jane Marshall, John Saunders, E. Jane Marshall and David Nutt. Oxford University Press. ISBN13: 9780199539338
Mechanisms and Treatment of Alcohol Dependence and its Sequelae: a 2009 Update
Dr Saunders used a single, complex case of alcohol dependence to introduce an overview of neurobiological mechanisms underlying the development of dependence; and a case of fetal alcohol syndrome, as an example of alcohol related neurodegeneration.
Patient K was a woman in her early 40s who had lost a promising professional career and marriage in her late 20s after a severe neurological insult left her with cognitive impairment, gait disturbance and dysarthria. Five years later she had married again and entered into a new phase of life, but gradually developed alcohol dependence with regular consumption of 120-180g/day. Among risk factors were a family history (father) of alcoholism, and the trauma and loss resulting from her disability and possibly also the brain injury itself. Treatment followed a not unusual course of withdrawal management followed by periods of abstinence supported by acamprosate and/or naltrexone, each time with subsequent relapse.
Twin studies show about 50% of population variance of alcoholism to be genetic; there is a tendency to father-son and mother-daughter vectors. Cohort longitudinal studies point to developmental factors especially childhood abuse, be it physical, sexual, or repeated mental abuse, along with other trauma, for example PTSD. At a sociological / anthropological level, cultural, socioeconomic and regulatory factors are also important.
What are the mechanisms of dependence? While workers in the field of addiction are becoming fairly familiar with the idea of meso-limbic reward pathways, our speaker gave us a more comprehensive understanding of the neurobiological mechanisms of dependence by including also mesolimbic stress, and frontal inhibitory, control systems.
Among the neuronal reward circuits, dopaminergic pathways are especially important for psychostimulants and nicotine, and opioid pathways for alcohol and opioids. When such substances are repeatedly or continuously used, the natural activity of these systems is suppressed. A negative mood and motivational state develops: more and more of the substance is required merely to maintain the normal state, while other normally "rewarding" activities become blunted. The substance use can be said to have “high-jacked” the reward system.
At the same time, with repeated substance use the balance is re-set between brain stress and anti-stress systems, through stimulation of pathways involving the excitatory neurotransmitter glutamate and CRF (corticotrophin-releasing factor) and suppression of GABA and ‘Neuropeptide Y’ circuits. The stress systems become “supercharged” to respond to exposure to psychoactive substances and cues or trigger for the substance use.
Finally, with repeated substance use there is progressive impairment of pre-frontal-mesolimbic inhibitory pathways, with impairment of executive functioning, decision-making and insight.
In combination, suppression of reward systems, their "high-jacking” by substance use, and “supercharging” of the stress systems to respond to psychoactive substances and their associated cues, generate a powerful “internal driving force” which is little influenced by voluntary control, because of impaired frontal inhibitory systems.
At this Concord Seminar, when an audience member asked about the situational and emotional triggers for alcohol use in patient K, Dr Saunders responded: "It doesn't matter what the triggers are, she is dependent. There is an overwhelming, tsunami-like force driving it."
Pharmacotherapies for alcohol dependence, included much the same list as when Dr Saunders last spoke to us in 2005, though the evidence base has developed since then.
Naltrexone (blocks opioid pathways for alcohol reinforcement/reward; see below)
Acamprosate (restores balance to GABAergic/glutaminergic stress responses; see below)
Topiramate (similarly, restoring balance to GABAergic/glutaminergic pathways in the corticomesolimbic system; several randomised trials from USA, and Finland)
Disulfiram (aversive agent, unpleasant reaction on alcohol ingestion; see below)
Ondansetron (selective 5-HT(3) (serotonin) antagonist [‘Zofran’] may be effective for patients with early-onset alcoholism, associated with greater serotonergic abnormality & greater mood disturbance, including depression, anxiety, hostility and antisocial behaviors)
Baclofen (GABA-B receptor agonist, reducing craving and alcohol intake in small trials)
Buspirone (for alcohol dependence and comorbid social anxiety)
SSRIs (for underlying or residual depression, and to be avoided in young alcoholic men with depression/suicidality, in whom they may make matters worse – the reason for this is not entirely clear, but see ondansetron above)
While a Cochrane review (Srisurapanont et al, 2005) for naltrexone gives clear evidence that relapse into alcohol dependence is reduced by some 36%, the Cochrane review of acamprosate has not yet reported, and there have been negative findings from recent US and Australian studies. There have been two important studies of combined naltrexone and acamprosate for alcohol dependence, with some evidence of benefit from the combination in Kiefer et al (2003) but little at all for acamprosate from the COMBINE Study (eg Anton et al 2006; Donovan et al 2008). There is also good evidence for improved outcomes for disulfiram, provided it is supervised.
With huge variability in findings from different studies, especially for acamprosate, Dr Saunders notes that exploring the heterogeneity of these studies may be a key for furthering our understanding and planning further research. Much may be lost by the reductionism of meta-analysis. Meanwhile, naltrexone tends to be his first line choice for alcohol dependence.
Some basic contrasts between the use of naltrexone and acamprosate are listed here.
Initiation: for naltrexone, when abstinent or when drinking; for acamprosate only when abstinent.
Onset of action: for naltrexone within 24 hours; for acamprosate one week
Pattern of drinking: for naltrexone, alcohol dependence with binge pattern; for acamprosate, alcohol dependence with regular daily drinking
Triggers to drink: for naltrexone, smell, taste, initial consumption of alcohol; for acamprosate, geographical, interpersonal and emotional triggers
Sub-type of dependence: for naltrexone, early onset & strong family history; for acamprosate, later onset.
Genetic markers: for naltrexone, having opioid receptor gene (OPMR1- Asp40 allele)
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We were then introduced to a difficult clinical situation. An addiction specialist noticed by chance, while treating a pregnant alcoholic woman abstinent in early recovery, that a previous child had previously unrecognised fetal alcohol syndrome. Ethical issues about contacting that child’s doctor, or community services, the potentially devastating impact of informing this woman at such a time and almost certainly precipitating relapse and worse outcomes led to lively discussion. Happily in this case the fine line was successfully trod.
Fetal Alcohol Syndrome is at the most severe end of the range of Fetal Alcohol Disorder Spectrum (FASD). The features are
1. maldevelopment of the mid face, including a small flattened nose, wide-set eyes, epicanthic folds, a thin upper lip, and absent philtrum
2. microcephaly, mental retardation (average IQ 70) and behavioural abnormalities
3. congenital cardiac abnormalities
Learning difficulties become apparent in childhood, and there is no improvement in IQ over time. There are social interaction deficits, but more typically the children are over-friendly to peers and adults, and so-called moral deficits – high prevalence of promiscuity, sexually transmitted diseases in teen years - may be attributable to these factors.
Management consists of teaching adaptive living skills, (such as to be appropriately guarded with strangers and certain family members), educational placement, speech and language services, occupational therapy and vocational guidance, and advocacy as needed.
This brought us to the matter of alcohol and neurodegeneration, especially in young people. We are reminded that brain development continues until at least the age of 21. Particularly that during this time, but also afterwards, neurones and their connections are in a state of dynamic flux, of which ongoing neurogenesis is an essential part.
In experimental animals, with increasing alcohol exposure there is increased differentiation of neural stem cells to oligodendrocytes and astrocytes and reduced differentiation to neurones, with blunting of dendrites, and inhibition of neurogenesis as a primary mechanism of neurodegeneration. In Fetal Alcohol Syndrome there is not only major structural damage in the 1st trimester but a quantitative decline in the number of neurones in the 3rd trimester through inhibition of neurogenesis (in which tobacco smoking, diet and vitamin deficiencies probably also play a role).
For further reading, we recommend Bankole Johnson's review:
Johnson BA. Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings.Biochem Pharmacol. 2008 Jan 1;75(1):34-56. Full text available free at http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17880925
Also, Dr Saunders won't mind us giving a plug for a new "concise and practical guide for students and practitioners of medicine and other health professions who come into contact with people with substance use disorders." Addiction Medicine. Editors Noeline Latt, Katherine Conigrave, Jane Marshall, John Saunders, E. Jane Marshall and David Nutt. Oxford University Press. ISBN13: 9780199539338
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