NON-OPIOID DRUG SIDE EFFECTS: COGNITIVE EFFECTS OF CENTRALLY ACTING DRUGS WHEN ? FOR PAIN

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NON-OPIOID DRUG SIDE EFFECTSCOGNITIVE EFFECTS
OF CENTRALLY ACTING DRUGS WHEN ? FOR PAIN

• High level literature evidence almost
  non-existent
• Cochrane Data base of systematic reviews etc.
• Other sources
• Literature search
• Road accident research Units
• Sleep Disorder Units - sleep hygiene, OSA

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NON-OPIOID DRUG SIDE EFFECTS

• Drugs
• Antidepressants, anticonvulsants,
  benzodiazepines,b-blockers, antihistamines
• Cognitive effects data
• Usually available for primary indication
• Similar data for pain patients is sparse
• Medline search (1985 - present)
• Few meta-analyses for above drug classes
• Issue of combination therapy
• Poly ? treatments - possible drug interactions
• ? Observed cognitive effects are due to which
  drug
• Data more likely to be available for add on
  therapy

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METHODOLOGICAL ISSUES (1)

• Consider the cognitive effects of untreated or
  poorly treated 1o indication
• Depression, epilepsy, pain
• Superimposed impact of drug ? needs to be
  evaluated against this background
• Volunteer studies - many problems
• No underlying pathology
• Short ? period (max 7 days) low drug doses
• Composition of neuropsychological test battery
  (also an issue for patient studies)
• Timing of tests

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METHODOLOGICAL ISSUES (2)

• Ideally need randomised, double blind, placebo
  controlled monotherapy in optimised doses
  resulting in a functional pain free individual
• Realistically, cognitive effects assessed at
  steady state after months of therapy
• Time dependent changes in cognitive effects,
  worse after initiating therapy
• Studies of newer agents often controlled by
  patent holder

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THE BOTTOM LINE !!

• Impact of Rx drugs on return to work
• Particularly high risk occupations
• Some investigations re a battery of tests to
  administer in work place to predict risk
• Driving Motor Vehicles
• Volunteer studies and examination of accidents
• Lack of congruence between volunteer (ie
  laboratory studies) and road accident data
• Lab studies deficient in both directions
• Cognitive function
• Circadian changes throughout the day
• Sleep hygiene has an influence on the above
• Cognitive function ? with ? age (test dependent)

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DRIVING MOTOR VEHICLES

• Volunteer Studies
• Simulated driving
• reaction time attention span assessments
• Neuropsychological quentionnaires
• Effects related to equivalent BAC (extensive
  data)
• Accident data - qualitative assessments of
  alcohol, licit and illicit drugs in
• Accidents involving death
• Accidents involving injury
• Random road-side sampling
• Frequently blood concentrations are measured

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2nd. GENERATION DRUGS

• Usually show efficacy in 1o indication equivalent
  to first generation drugs (rarely are they more
  effective)
• Maybe more potent (? advantages)
• Pharmacokinetic advantages (leads to better
  compliance)
• Usually superior adverse event profile
• Preferred because of the balance between efficacy
  and side effects

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ANTIDEPRESSANTS (TCA Vs SSRIs)

• TCAs - meta-analyses demonstrate significant
  analgesic effect (NNT 3)
• Mechanism of action
• Inhibit reuptake of noradrenalin and 5HT
• Cholinergic receptor inhibition ? dry mouth,
  constipation, urinary retention, blurred vision
  and cognitive dysfunction
• H1 receptor inhibition ? sedation, impaired
  motor function
• a1 adrenergic receptor inhibition ? imbalance,
  impaired co-ordination, orthostatic hypotension,
  tachycardia

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ANTIDEPRESSANTS - SSRIs

• Do they work (? analgesic effect), meta-analyses
  not as favourable (small patient numbers ? less
  adequate data base)
• Selectively block 5HT reuptake (presynaptic
  neurones)
• Adverse events
• nausea, headache, anxiety, nervousness, insomnia,
  drowsiness, fatigue, sexual function
• Patient studies (depression) - side effects
• Sertraline, amitriptyline versus placebo
• Short term (2 - 3 weeks) - sertraline
  amitriptyline
• Long term - sertraline ?, amitriptyline ?

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TCAs VERSUS SSRIs - COGNITIVE EFFECTS

• Volunteer studies
• TCAs - 10 - 20 acute impairment
• Paroxetine - no impairment compared to placebo
• Patient studies (cf aged matched controls)
• TCAs - lower cognitive function
• SSRIs - improved cognitive function (shows
  impact of disease on cognitive function)
• Brake reaction time (BRT)
• assesses inter alia, sedation
• SSRIs - do not effect BRT
• TCAs - result in extra stopping distance
  equivalent to a BAC of 0.08

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ANTICONVULSANTS - ESTABLISHED DRUGS

• Minor cognitive changes in short term (4 months)
• Relative to pre? state (cognitive deficits)
• Cognitive function ? on drug withdrawal
  (carbamazepine, valproate)
• Carbamazepine results in less cognitive deficits
  than phenytoin

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ANTICONVULSANTS -GABAPENTIN LAMOTRIGINE

• Add on therapy Vs placebo (epilepsy)
• No effects on tests of concentration, memory or
  psychomotor performance
• Drowsiness with gabapentin (gt 2.4 gm / day)
• Effective doses (seizure frequency ? )
• Volunteer studies ( Vs carbamazepine, phenytoin)
• Good design (r, db, crossover)
• Comprehensive battery of tests
• New drugs better - gabapentin (25 variables),
  lamotrigine (50 variables)

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BENZODIAZEPINES

• Profound effects on cognitive function ability
  to drive
• Cognitive function ? on drug withdrawal
• Still significant deficits at 6 months (cf age
  and IQ not anxiety matched controls)
• Attention,visual-spatial ability compromised the
  greatest
• Patients lack insight to these effects
• Role in pain patients highly questionable
• Implications for driving, rehabilitation

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DRUG IMPACT ON SLEEP

• Consider influence of pain (fatigue, cognition)
• Drugs
• TCAa -? sleeptime (TST), effects ? over time
  are more profound in elderly
• SSRIs - ? w, ? TST, performance ? or mild ?
• Antipsychotics - ? sedation
• Benzodiazepines - ? sedation, ? performance, ?
  TST (but with rebound insomnia on cessation)
• b-blockers -? w, ? insomnia nightmares (more
  common with lipophilic drugs in elderly), few
  consistent neuropsychological effects
• Older anticonvul -? TST, mild, mod ? performance
• Newer anticonvul - little polysomnographic lab
  data avail and only as add on therapy

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ALCOHOL CANNABINOIDS - BEHAVIOURAL EFFECTS

• Low blood concs effect psychomotor test
  performance (range of tests)
• Higher concs ? negative effects
• Same blood concs. - more profound effects in
  absorption cf elimination phase
• 50 total negative effects
• BAC 0.073 THC 11 ng / ml
• Different ranking between drugs
• Alcohol - driving test most sensitive (THC
  6th.)
• THC - tracking test most sensitive (Alcohol
  5th.)

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DRUGS MOTOR ACCIDENTS

• No uniform effects across drug classes (volunteer
  studies)
• Alcohol illicit drug extensively studied
• Some motor accident data for Rx illicit drugs
• Attempt to relate this data to a qualitative
  expert opinion re impact of drugs in causing
  accident or death (again, alcohol illicit drugs
  data more available)
• Measured drug conc - assay methodology issues
• Therefore, conservative estimates

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PRESCRIBED DRUGS - ROAD ACCIDENTS

• Subdivided into fatal injured drivers
• Fatal accidents
• Alc (32), drugs (illicit Rx, 16.3), benzo
  (8.5), barbit (1.2), methadone (0.4), opiates
  (2.8)
• Similar percentages for injuries
• Suspected driving under the influence
• 42, 82, 38, 4, 12, 3.6 TCAs (4.1)
• Estimated 3.5 - 7 of accidents caused by
  psychoactive medicines
• Diazepam - RR 3.1 injurious accident

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DRIVING WORKPLACE SAFETY - TEST BATTERY

• 10 Computerised tests evaluated
• 40 Volunteers with BAC ranging from 0.01 - 0.12
• Performance decrements statistically correlated
  to BAC
• 97 Specificity (assessed being fit / total fit)
• gt 80 Sensitivity (identified unfit / total
  unfit) at high BAC
• 60 Sensitivity at low BAC
• Clearly a good concept, but there is a long way
  to go

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CONCLUSIONS

• Inadequate data re cognitive effects of
  non-opioid drugs Rx for pain
• Need to consider cognitive effects of pain
• Issue of poly drug treatment of pain
• 2nd. Generation drugs are better, BUT do they
  have equivalent analgesic effects
• Benzodiazepines have profound effects and have no
  place in treating pain
• Hope of test battery to predict workplace safety
  driving still requires significant development