27 September 2012

New York Grand Rounds: ADHD and dependency; acupunture in addiction syndromes; ketamine in severe depression.

Wednesday, 2 May 2012 10.30am Grand Rounds.

I was privileged to hear three registrars at Bellevue Hospital in Manhattan discuss literature reviews on three interesting topics.

Dr Erin Zerbo spoke on ‘ADHD and Co-Morbid Substance Abuse’

Dr Crystal Tholany dealt with ‘Acupuncture in dependency practice’

Dr Joseph Kwon addressed ‘Ketamine for Treatment of Depression’

1. ADHD & Co: Dr Zerbo.

We learned that ADHD was extremely prevalent, affecting 6-9% of children with ½ to 2/3 of cases persisting into adulthood, making ~4.4% of US adult population (~8 million victims).

Since 10-30% of adults have substance use disorder (SUD) there is a very large overlap of these groups. This was shown starkly in The National Comorbidity Survey Replication (n=3000) where prevalence of ADHD in those with a SUD was 11% while in those without SUD it was only 4%. The same survey showed that SUD was present in 15% of those respondents with ADHD but only 5.5% of those not having the ADHD. Four other studies (each 100-300 subjects) showed a high prevalence (10-24%) of DSM diagnosed ADHD in those with alcohol, cocaine and opioid dependency.

This information puts ADHD clearly in the scope of dependency health workers although on the other hand almost 90% of ADHD subjects have no substance use disorder (SUD) at all. It was emphasised by Dr Zerbo that as well as having a more severe and more prolonged course, ADHD subjects with addiction are also less likely to fit in with existing treatments despite such treatments being known to be just as effective in this population group.

I was interested to learn that those with ADHD are likely to use the same spectrum of drugs as others with drug use disorders and no ADHD. However, the drug use is often from a younger age and is more severe with more co-morbid psychiatric and behavioural disturbances.

The criteria for diagnosis of ADHD included six symptoms of inattention, hyperactivity or impulsivity for more than 6 months, dating from before 7 years of age, in two or more settings involving clear impairment and in the absence of other psychiatric reasons for the symptoms. In adults one would expect: low frustration tolerance, chronic conflicts with peers and authorities, stubbornness and impulsivity (which are major obstacles for treatment).

To make the diagnosis in adults one would ideally (but not necessarily) have the substance use disorder stabilised for at least one month before making the diagnosis. Differential diagnoses include thyroid disease, sleep disorders, bipolar disorder, generalised anxiety, chronic drug or withdrawal related syndromes.

Treatment using stimulants, antidepressants, noradrenergic agents, etc can be very effective for ADHD symptoms but rarely does anything for the SUD directly. Hence opiate maintenance or other pharmacotherapy for SUD should be used just as insulin might be used if the patient were diabetic. Dr Zerbo has made the point that appropriate and early treatment of the ADHD will ensure lower drop-out rates from treatment, including opiate maintenance where this is necessary.

A case history given raises issues of polypharmacy as a complex in-patient from the Bellevue Hospital ward was discharged after stabilisation with the following medications: methadone 120mg daily, dextroamphetamine 60mg daily (slow release), gabapentin 300mg tds, hydroxyzine 25mg nocte (sedating antihistamine) and valproic acid 500mg bd. I was told by staff that such cases are not uncommon but reminded that Bellevue tends to attract some of the more difficult cases, being a tertiary referral centre.

A colleague from California tells me that it can be a regulatory nightmare getting permission to prescribe opiate maintenance along with stimulants even though there is obviously a group of patients who need both drugs. He said that only in the Veterans Administration setting was it possible to give comprehensive care in his experience.

Conclusions given by Dr Zerbo:

1. Patients with ADHD are at higher risk for SUD, and have a more severe and prolonged course if they develop SUD.

2. ADHD symptoms can be a significant barrier to effective SUD treatment.

3. Pharmacological treatments for ADHD are effective in patients with SUD; they have not been found to be addictive or to worsen the SUD (even while active).

4. ADHD is often under-prioritized, which can lead to greater morbidity for these patients and a longer time to remission.

My own conclusion is that we must be under-treating some of our dependency patients unless we have a proportion (at least 5% probably) taking prescribed stimulants. If we are not comfortable with that then we are not comfortable with evidence based medicine. I am not proud to say that we only have had three or four such cases in our practice in Sydney over the past decade. The regulatory hurdles are immense.

For more information on this subject: http://dependencyseminars.blogspot.com.au/2008/07/adult-adhd-substance-use-disorders-dr.php4

2. Dr Crystal Tholany spoke next about acupuncture in the treatment of dependency and withdrawal syndromes.

We were given a description of acupuncture and some proposed mechanisms for its apparent effectiveness in various medical settings. We were given the historical context for following thousands of years’ of use in China, its introduction into American medicine and especially in the treatment addiction and withdrawals and the several studies that have been published. There were connections through Japan, Hong Kong and the Bronx. All eyes were on whether it was better than placebo. Many modern settings use electronic as well or instead of mechanical stimulation to the fine needles inserted into the body.

It was found that acupuncture could lessen withdrawal symptoms dramatically. However, this was not evidence based and the effect wore off quickly once the acupuncture was ceased.

Trials show no change in symptoms after treatment stops but some changes remained in PET scans and pathology with several proposed mechanisms.

We were also told about ‘HANS Acupoint’ nerve stimulation which has some followers using sticky patches rather than needles at specific anatomical points found on charts. Studies showed much lower doses of methadone or buprenorphine were required to abolish withdrawal symptoms (published in Chinese Journals of addiction and pain): 1mg versus 13mg bup and 50mg methadone vs. 200mg ‘total of doses requested’ over a 14 day period.

There are also some unconvincing but interesting animal studies. In some intriguing para-placebo studies groups were randomised to receive either “sham” acupuncture of the real thing. This was the closest one might get to a RCT, showing that in addiction cases no differences were shown for symptoms yet some changes were noted on MRI scan findings. In fibromyalgia cases, however, there were some significant improvements in those receiving the true acupuncture under the blindfold.

So, like AA, therapeutic communities, ten-day detoxification and numerous other respected interventions, acupuncture remains a folk treatment and non-evidence based to date. After centuries of use it should not be dismissed but likewise it should not be recommended in place of known effective treatments regarding serious outcome measures including morbidity and mortality. Because this treatment has only been used quite recently in addiction it warrants further investigation, according to Dr Tholany. Naturally it must never be advised in preference to proven treatments like opiate maintenance but in those refusing such treatments and consenting to non-evidence based approaches it may a valid alternative.

3. Dr Joseph Kwon spoke about ketamine for treatment of depression.

Dr Kwon was the third of three senior registrars at Bellevue to deliver a brief paper at their Grand Rounds to which I was invited. Dr Kwon had performed a literature search and presented some history, pharmacology and made the case for this option to be investigated further and possibly used now under close supervision for treatment resistant cases of suicidal depression.

The reason this subject was broached was the recent focus on suicide prevention and the delayed onset of most current forms of treatment for depression. There was also a group of treatment resistant individuals who failed to respond to either antidepressants or ECT. These included both endogenous depression and those with histories of bipolar disorder.

Ketamine was discovered as a shorter acting form of phencyclidine in 1962, having dissociative anaesthetic properties as well as uses in local anaesthetics and analgesia. It was found to have sympathomimetic effects, causing a trance like state at high doses and had a low incidence of respiratory depression. The half life was 2 hours.

The drug’s effect is largely on inhibiting the glutamate system and a Wikipedia page indicates that it shares this property with nitrous oxide, alcohol, methadone, propoxyphene, tramadol, PCP, ibogaine and numerous other substances.

There are groups interested in this subject at Mt Sinai Hospital in New York as well as Bethesda Maryland and in the Netherlands (there was also a paper from New Zealand I noted). Numerous publications of small trials were cited to justify further work and even to use this treatment off-label in certain severe cases at the present time. There has been at least one RCT in an add-on trial with other observational studies being reported, largely very positive in their outcomes with low rates of side effects.

We were told by Dr Kwon that research had shown depression to be associated with increased glutamate in the occipital cortex and reduced levels in the anterior cingulate gyrus. Animal experiments with stressed mice showed better coping with shock when pre-treated with ketamine as also seen with other antidepressants (at least that was the inference).

We were informed that ketamine is fifth on a relatively long WHO list of ‘essential drugs’ for medical purposes.

A small number of invivo human trials were cited: infusions in emergency room situation were very effective apparently as promptly reversing many signs and symptoms of depression on validated scales. In cases of suicidality this type of intervention could clearly be life saving if used appropriately.

Small doses of ketamine (1mg/kg) were shown to improve postoperative depression (and also pain in depressed patients). Another three trials were mentioned involving single or repeated infusions, one with placebo control. No patient developed psychotic symptoms (schizophrenic patients were excluded).

Like morphine and other prescription drugs, it is also used as a mind altering drug recreationally. Taken at rave parties, for example, it seems to cause more dissociative symptoms than the much more popular MDMA. I was informed that it has become one of the most popular recreational drugs in Hong Kong in recent years.

I understand that some Australian centres use ketamine for acute analgesia in patients who are taking buprenorphine (presumably due to resistance to morphine from the antagonist properties of the maintenance drug). According to a colleague in London it could also be useful in those taking naltrexone. I note that ketamine is available in Australia as a parenteral anaesthetic/analgesic under the trade name Ketalar, available in vials for injection of 200mg per 2ml liquid. Product information states that doses must be titrated individually but that 150mg injected intravenously can cause ten minutes of surgical anaesthesia.

It is the writer’s view that ketamine could do with a ‘White Knight’ like Reckitt Benckiser which developed buprenorphine as a treatment for opioid dependence. As an old drug, ketamine is of little interest to drug companies in its present state. However, with some manipulation and focussed research a new patented version could be part of the way to both profits and improved treatment options. With the benefits promised by Dr Kwon’s presentation I would buy stocks in any company working in this direction.

As well as Dr Marc Galanter, head of department, and addiction psychiatrist Dr Phoebus Dhrymes, veteran dependency advocate Charles Winick was in the small audience at Bellevue for this morning session. As it happened, Winick gave a talk I attended at Columbia University the following week outlining some parallel issues with fundamental research on rehabilitation which, like acupuncture and AA, is not easily amenable to controlled trials although some have been attempted with positive outcomes. Yet another coincidence was that we were both due for appointments at the Drug Policy Alliance later that day - let’s share a cab! “Only in New York!” There were more stories on request of security in New York hospitals and other institutions these days … food in New York … ‘coffee’ in New York … and more.

Written by Andrew Byrne ..

Clinic web page: http://methadone-research.blogspot.com/

A month in New York: http://andrewbyrneinnewyork.blogspot.com/

New York in 1922 from grandfather: http://bpresent.com/harry/code/09n_new-york.php

Lord Howe Island story: http://www.redfernclinic.com/c/2007/10/lord-howe-island-naturalists_4153.php4

Our butterfly collection: http://schraderbutterflies.blogspot.com/

Shylock and anti-Semitism: http://cantorialcrossoverculture.blogspot.com/2011/04/shylock-shakespeare-and-jews-anti.html