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

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

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  1. NON-OPIOID DRUG SIDE EFFECTS:COGNITIVE 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

  2. 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

  3. 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

  4. 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

  5. THE BOTTOM LINE !! • Impact of  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)

  6. 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

  7. 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

  8. ANTIDEPRESSANTS (TCA V’s SSRI’s) • TCA’s - 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

  9. ANTIDEPRESSANTS - SSRI’s • 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 

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

  11. 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

  12. ANTICONVULSANTS -GABAPENTIN & LAMOTRIGINE • Add on therapy V’s placebo (epilepsy) • No effects on tests of concentration, memory or psychomotor performance • Drowsiness with gabapentin (> 2.4 gm / day) • Effective doses (seizure frequency  ) • Volunteer studies ( V’s carbamazepine, phenytoin) • Good design (r, db, crossover) • Comprehensive battery of tests • New drugs better - gabapentin (25% variables), lamotrigine (50% variables)

  13. 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

  14. DRUG IMPACT ON SLEEP • Consider influence of pain (fatigue, cognition) • Drugs: • TCA’a - sleeptime (TST), effects  over time & are more profound in elderly • SSRI’s -  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

  15. 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.)

  16. DRUGS & MOTOR ACCIDENTS • No uniform effects across drug classes (volunteer studies) • Alcohol & illicit drug extensively studied • Some motor accident data for  & 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

  17. PRESCRIBED DRUGS - ROAD ACCIDENTS • Subdivided into fatal & injured drivers • Fatal accidents • Alc (32%), drugs (illicit + , 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% & TCA’s (4.1%) • Estimated 3.5 - 7% of accidents caused by psychoactive medicines • Diazepam - RR = 3.1 injurious accident

  18. 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) • > 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

  19. CONCLUSIONS • Inadequate data re cognitive effects of non-opioid drugs  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

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