Interaction and Emergency in Addiction: causes and consequences

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1 Interaction and Emergency in Addiction: causes and consequences Stephan Walcher CONCEPT Center for Addiction Treatment Munich Strasbourg Conference Group Pompidou 2010

2 First thing to learn in addiction-medicine: EuropeanRescueCouncil guidelines! Basic Life Support

3 Emergencies and different drugs: -Withdrawal -Intoxication

4 Speed (XTC, Amphetamine, Slimmers ) Cocaine, Crack Hallucinogens (LSD, MK, Magic Mushrooms and other Natural Drugs ) Tranquilizer, Sedatives (BDZ, Barbiturates) Opiates (H, Analgetics, synth. Designs, Methadone, DHC, s.c. sl. r. Plasters ) Antidepressives, Neuroleptic (TCAs, MAO-Inhibitors + others) Alcohol

5 Withdrawal Opiates: Symptoms: restless, dysphoric. aggressive patient, tachycardia, sweating, spontaneous tears, hyper salivation, diarrhea, vomiting, mass. Chills and feeling cold, tachypnea, piloerection, embolism, rhythm disorders, enhanced reflexes, potential withdrawal cramps and fits (rare) Emergency treatment: Talk down Clonidine (slowly mg) Doxepine or Mirtazapine or light sedatives (Diazepam 10mg) PPIs (40mg pantoprazole) + 5-HT-antagonist (5mg Navoban) Ibuprofene for joint/muscle-pain (4-1200mg/d) Help and motivate to find detox-clinic. No primary agonist substitution for unknown patient (although patient loves you for that) General guidelines for BLS Walcher et. al. 1998, Freye 1996 Backmund 2002

6 Intoxication Opiates: Symptoms: Pale, sleepy, apathetic patient, low muscular tonus, reduced reflexes, miosis, respiratory depression, cyanosis, bradycardia, collapse, vomiting, aspiration, brain- and pulmonary edema, ARDS, coma, embolism Compartment-syndrome, peripheric paralysis, burns Emergency intervention: BLS-guidelines: check respiration - circulation - consciousness Stabile lateral position securing respiration if necessary intubate or use LAMA or esophagus blocking tube, i.v.-access arm/jugular/subclavian cc cristalloids If really necessary: Naloxon (0.1mg/min up to 4mg) but: be aware of rebound (Naloxone halflife min) Be aware of precipitated withdrawal and => drugseeking patient Check for additional resp.depressors! => BZD, TCA, neuroleptics Walcher et. al. 1998, Freye 1996 Backmund 2002

7 Withdrawal BZD-Barbs: Symptoms: restless, absolute sleepless, aggressive, potentially precomatic patient, phobic and frightened, tremor, delirium, paranoid psychosis, hyper sensibility, High risk of fits (Grand Mal), paresthesia, nausea and vomiting, depersonalisation, dysarthrie, nystagm, cephalgia Emergency intervention: Propylaxis or treatment of fits: Save lateral position (head!) If necessary clonazepam or phenytoin Follow general guidelines of BLS Walcher et. al. 1998, Freye 1996 Backmund 2002

8 Intoxication BZD-Barbs: Symptoms: pale, sleepy, disoriented, apathetic patient, slow motion, coma (GCS<5) low muscular tonus, hyporeflexia, miosis, attenuated respiratory depression (esp. in combination with opiates), cyanosis,brain- and pulmonary edema, ARDS, collapse Compartment-syndrome, peripheric paralysis, burns (when long time in collapsed, unphysiological position) Emergency intervention: Follow BLS rules check respiration - circulation - consciousness Stabile side position, if necessary secure respiration (see opiates) Give crystalloids 1000 cc (see opiates) If necessary carefully give Flumazenil (0.2mg/min bis 10mg) be aware of rebound and potential fits Walcher et. al. 1998, Freye 1996 Backmund 2002

9 Withdrawal Stimulants: Symptoms: dysphoric, exhausted patient, sleepy patient tremor, hunger, chills, dyspnoe depression, potentially suicidal (esp. Cocaine-injectors) Emergency intervention: Put asleep, talk down and watch Evaluate carefully suicidal tendency Mainly psychic withdrawal but in ivdu and combined with LSD/BZD/Opiates also somatic Walcher et. al. 1998, Freye 1996 Backmund 2002

10 Intoxication Stimulants: Symptoms: Early stimulation: logorrhoic, nausea, vomiting, restlessness, headache, cocaine-ants, hallucinations, fever, arrhythmia, hypertension, panic-attacks, hyperventilation syndrome, Mania, constipation Late stimulation: hyperreflexia, convulsions and fits, malignant encephalopathy, malignant hyperthermia, loss of consciousness, coma, peripheral and central cyanosis, cheyne-stokes-respiration, cerebral infarction, brain and pulmonary edema In addition: collapse due to overheating and exsiccosis (XTC-Rave) Emergency intervention ART: Accept, Reduce stress, Talk-down. Rehydration (best cristalloids with 5% glucose + Vitamin B1) Propanolol, Lidocaine, Amiodarone (for HT and Arrhythmia) BZD (Agitation, fits) Follow BLS-guidelines Beware of additional intoxications (80% Alcohol, 25% opiates, 30%BZD-rest, 100% THC, 10% LSD) Walcher et. al. 1998, Freye 1996 Backmund 2002

11 Withdrawal Hallucinogenes: Symptoms: No withdrawal known so far, but urgent wish to repeat Can be dysphoric, sleepy or depersonalized / schizophrenic Emergency procedures: Psychic withdrawal, but dangerous in combination with stimulants (in one pill!) or other hallucinogens Most of hallucinogenic plants contain >50 alkaloids Watch and let recover Follow BLS Psychiatric and psychosocial support Walcher et. al. 1998, Freye 1996 Backmund 2002

12 Intoxication Hallucinogenes: Symptoms: tachycardia, nausea, dry mucosa, collapse hyperventilation syndrome, agitation, panic attacks, hallucinations horror trips, schizophrenic psychosis, acute depersonalisation, desorientation Secondary damage: Traffic and other accidents Flashback events, altered view Depersonalisation, schizophrenic and chron. depressive disorders Emergency intervention: ART: Accept, Reduce stress, Talk-down In acute psychosis or suicidal state admit to hospital Sedate with BZD only (initially) Don t forget potential rebounds Walcher et. al. 1998, Freye 1996 Backmund 2002

13 Withdrawal Psychopharmaceutics: Symptoms: Deep depression incl. suicidal state, apathic, fatigue, sleepless Urgent wish to relieve Emergency intervention: ART: Accept, Reduce stress, Talk-down Be ware in cases of combined withdrawal BZD Give adequate antidepressant

14 Intoxication Psychopharmaceutics: Symptomes: Dry mucosa, mydriasis, sweating, tachycardia, disorientation, ataxia, parkinson, constipation and bile-retention, resp. Depression, aspiration Arrythmias (hard to treat!), asystoly and ventricular fibrillation, heartinsufficiency EPMS and neuroleptic syndrome Emergency intervention: Remove drug (if necessary by gastric tube!) Biperidene for NeurolSy, BZD for cramps/fits, Physostigmine for EPMS Cristalloids, CPR until drugs are eliminated (up to 4 h) if necess. using hemofiltration or dialysis External (esophageal) or internal pacer Amiodarone and BZDs when necessary

15 QTc - alterations

16 Cause of Death: Overdose? (France) Number of Fatalities General population 1999 = 60,000,000 Start of massive Introduction of ORT mainly Buprenorpin in GPs offices Rapport OCRTIS, 1998

17 Torsade de pointes Polymorphic Ventricular tachycardia in the setting of QT prolongation: twisting of the points Prolonged QT with TdP

18 Sudden Death in the Community * 72 of 178 sudden deaths had methadone detected in their blood *Methadone levels of mg/l

19 QT- prolongation: drugs at risk Antiarrhythmics Kinidin, disopyramid, procainamid Na+ channels blocked action potential Amiodarone, sotalol, ibutilid, dofetilid K+ channels blocked delayed repolarisation QT-time/HR Psychopharmaceuticals TCA, antipsychotics Na+ channels blocked action potential length Other drugs Erythromycin, cisaprid, terfenadin, Methadone, LAAM, SL- Morphine and most μ-agonists

20 In vivo evidence for TdP due to methadone 15 case reports or series reporting TdP 17 episodes of TdP in high dose methadone Krantz Annals of Intern Med 2002 FDA MedWatch system, 43 cases of torsade de pointes associated with methadone; 8% were fatal and most involved doses of methadone exceeding 100 mg/day. Pearson & Woosley Pharmacoepidemiol Drug Saf One series showing recurrent TdP after re-challenge Patel Am J Cardiol, 2008

21 QT Interval Normal Ranges Suggested QTc Values for Diagnosing QT Prolongation QTc Values (msec( msec) ) By Gender Men Women Normal <430 <450< Prolonged (top 1%) >450 >470 Study Criteria >470 >490 QTc = QT/ RR; Adapted from Moss,A J. Am J Cardiol 1993; 72:23B-25B 25B From the Long QT Syndrome (LQTS) Registry

22 Implications Methadone remains a mainstay of opioid addiction treatment with reported reduction in mortality of up to 30% in IV drug users (Mt Sinai J Med 2002;64: ) Clinical benefit of Methadone needs to be weighed against the potential risks MHRA in the U.K. and CMMG in Canada have issued some preliminary guidance CSAT recommendations available December 2008 Buprenorphine appears to present less cardiac risk however access, cost and management are significant considerations

23 What should we do? Check baseline QTc prior to therapy; discuss history of cardiac disease If QTc <450, induce after discussion Repeat QTc at one month, or if dose >100 mg/day QTc >500, consider dose reduction, alternative therapy Avoid hypokalemia, drugs that block CYP3A4, drugs that prolong QTc Syncope merits consideration of cardiology consultation

24 Complications caused by -way of application -inappropriate use -diversion

25 Damage by way of application: IV-use Local damage: necrosis, abscess, empyema, vasculitis Regional damage: phlegmony, embolism, (art.) ischemia, DVT, enzephalitis, endocarditis, pneumonia Systemc damage: Sepsis (bacterial / fungal), DIC, ARDS BBV-Infections: (in ST-Patients) Anzahl Infektionstyp HCV HIV HCV_/HIV HBV HBV-/HIV HCV-/HBV-/HIV Reisinger 2006, Walcher OP Sucht 2006, Catania 2002

26 Damage by way of application: Infection > 90% of HCV-Incidence from IvDU Fälle pro Einwohner Jahr Viral Hepatitis Hepatitis A Hepatitis B Sonstige Formen (vorwiegend Hepatitis C) Robert Koch Institut 6/2003

27 Problems with product -variability: Contents: Variable amount of substance: 0-80% or mg MDMA (Eve and Rave 97, drug testing project Amsterdam 98), lack of Confident Dealer Composition: high % or pure additive: up to 7 subst. (MBDB, MDA, LSD) (Uni Wien 98) (mannitol, strychnine, baby powder, Phenobarb) (BKA + LKA-Repots ) Sometimes complete replacement of indicated substance (Speed for Cocaine, Ketamine for XTC) (BKA + LKA-Repots ) Composition: Different galenic composition => different peak and speed of action: 0.3-3h, dep. On carrier (talcum, lactose, starch) and coating (gummi arab., resinates, sugars) Walcher et. al. OP DGS-AM 1998, Freye 1996, Backmund 2002

28 Problems with user -variability: Disposition: Metabolism/CYP P450 (as mentioned before) Gastric milieu (ph), kind and amount of gastric contents Personal situation: stressed means slow metabolism, sleep means faster metabolism Cardiopulmonary condition (sports) = better Tolerance Sex: women have 30-50% less active metabolism => potentially fatal effect Fluid-supply: HK > 48% = exsiccated -> higher risk of embolization Walcher et. al. OP DGS-AM 1998, Freye 1996, Backmund 2002

29 Damage by way of application: others Sniffing: SC/IM: Smoking: transfer of BBVs (HCV/HIV/HBV), chronic and acute sinusitis, «stinknose», asthma, encephalitis, meningitis, sinus-vein thrombosis, septum-perforation, pneumonia Buprenorphine: will be registered as spray! transfer of BBVs (HCV/HIV/HBV), Abscesses (sc>iv), Sepsis, DIC, Thromboses, nerve- and vessel damage, soft-tissue defects Lung-damage: asthma, pneumonia, abscesses, toxic lungedema, emphysem, lung-fibrosis, ARDS, empyema, lung-cancer

30 What clients are we dealing with?

31 European epidemiology HCV/HIV HIV HCV Fontaa 2001, Haasen/Reimer/EMCDDA 2003, Toufik 1999

32 Behavioural disorders in AIDS and Cancer-patients Passik et al 2003

33 Adult Psychiatric Morbidity Survey 2007 Common Mental Disorders CMD levels relatively stable with 15% of adults meeting criteria and 7.5% had symptoms likely to require treatment A quarter of those with such disorders receiving treatment, mainly with medication Half of those with two or more disorders were getting some treatment 3% screened positive for PTSD 2009

34 Psychiatric Comorbidity in ORT German COBRA Survey 2007

35 We are dealing with: Multi-morbid patients: physical, psychological and social General chaos in life Chronic Childhood Adversity (PTSD) Dissocial personality-disorders (DPD) Social rejection and isolation: parallel society multiple (auto)-medication in course

36 What medication are we dealing with?

37 Use of Psychotherapeutic Agents Thousands of New Users 2,500 2,000 1,500 1, Annual numbers of new users of psychotherapeutics, Pain Relievers Tranquilizers Stimulants Sedatives NHSDA, 2002 The National Household Survey on Drug Abuse. Non-medical Use of Prescription- Type Drugs among Youths and Young Adults. January 16, Substance Abuse and Mental Health Services Administration. US Dept of Health and Human Services

38 Rising role of Methadone in DRD US national institute of statistics

39 Death on overdose in IvDU: coroners findings (Ger) Reason of death 2004 % 2005 % 2006% 2007% Heroin 36% 31% 34% 40% Heroin + other drugs 19% 18% 22% 23% Cocain 3% 2% 2% 2% Cocain+other drugs 6% 6% 10% 9% Amphetamines 1% 0% 0% 1% Amphetamines + other drugs 2% 1% 2% 2% Ecstasy 1% 0% 0% 0% Ecstasy + other drugs 1% 1% 1% 0% Med /ORT-medication 10% 4% 3% 6% Tranq + Alk + ORT-med 30% 24% 22% 19% Other (sc 4 and unknown) 4% 9% 10% 10% BKA, DHS 2009 v. Meyer et. Al. 2008

40 Interindividual Metabolism ORT

41 Opiate-metabolizm: Cytochrome LIVER (CYP1A2) CYP2D6 CYP3A4 (CYP2C9) (CYP2C19) INTESTINES CYP3A4 Shinderman 2002

42 : Opiate-metabolizm: Cytochrome Enzymes Interindividual Inducible Genetic Variability by Drugs Polymorph. CYP2D6 > 1 to 100 NO YES CYP3A4 ~ 1 to 30 YES (YES) Wong et. Al. 2002

43 Full Agonist vs. partial Agonist in ORT: dose-action-relation Doxey et al 1982, Ling 2007

44 How are opiates interfering with other drugs?

45 Concomitant drugs We must be very careful when we prescribe more than one drug (or when we know that somebody else does ) At CYP-450 metaboliser prescribed drugs may: speed up (induce) or slow down (inhibit) the metabolism of the other drug(s) This could result in: decreased blood plasma levels elevated blood plasma levels higher doses required for same effect may be toxic and lead to overdose

46 Impact on Cytochrome System Induction of CYP450 3A4: Barbiturates, Carbamazepine, Phenytoin, Antibiotics:, HIVmedicaments, substances enhancing tolerance Inhibition of CYP450/3A4: HIV-medication, SSRIs, Makrolides, Methadone, Midazolam/BZD Methadone is metabolized at a multitude of CYP-450-enzymes Buprenorphine is >95% metabolized at CYP450 3A4 clinically there is much less interaction on CYP-450 Nutt 2006, McCance-Katz 2006

47 Opioid Therapy in BBVs Opioids and antiretrovirals metabolized by CYP 450 (especially 3A4) CYP-450 inducers: opiate withdrawal? CYP-450 inhibitors: opiate toxicity; antiretroviral toxicity perceived as opiate withdrawal? Find the right combination Detox the patient (eg. UROD) Change ORT agent

48 Drug Interactions: what does that mean to BBV-Treatment? Impaired compliance with treatment Viral resistance Lack of efficacy Severe impact on Comorbidity Illicit drug use with toxicity (+ further interactions) Direct Toxicity, drug related death

49 Clinical relevance of interactions

50 OD in ORT ORT-patients: highly reduced risk to die on overdose Methadone/LAAM/MO have a high μ - agonistic activity. action (kick) or side-effects (resp. depression) follow an exponential dose / effect-ratio + μ-receptor down-regulation. Buprenorphin => additional effect and OD only with maximum doses has much lower μ - activity + κ - antagonism Ceiling effect => no further effect above 32 mg (RR, drug ) Much higher receptor affinity: other opiats can t dock on Gölz 1995, BAS 2001, Lintzeris 2002

51 Tolerance and loss of tolerance Buprenorphine has: high affinity slow kinetcs partial antagonism => no down-regulation of µ-receptors means: lower addiction-potential milder withdrawal reduced speed of adaptation/tolerance but also: easier loss of tolerance Negus, Woods 1995 Zaki et al 2000

52 Tolerance and loss of tolerance Danger of reducing tolerance: High BMI: lower metabolisation and means of compensation (Pickwick-syndrome) Lower level of substitution: high rate of receptor-occupancy => lower extra-effects for on-top-use (kick, RD) SEX: females have lower tolerance Consuming illness: cirrhosis, cardial insufficiency, ventilation-disorders Loss of tolerance-enhancing substances: Cocaine, Amphetamines: analeptic counterweight to resp. depression but shorter half-life

53 BZD-use in ORT

54 Why do IvDUs use BZDs? Anxiety disorders Lifetime (ECA, NCS) General population 14 25% Heroin users 32% Dependent heroin use is stressful! Self-treatment of opiate withdrawal 89% of treatment seeking heroin users reported using other drugs to relieve opiate withdrawal in previous month 61% other opiates, 50% BZDs (Germany 68%) 39% (Germany 88%) cannabis, 32% alcohol To get stoned Backmund 1999, Walcher et. al. in BAS-guidelines 2009, Lintzeris et al, 1994

55 BZD Use in MT: consequences ODs often involve BZDs 50 80% among heroin-related deaths (40 80% among methadone-related deaths) Up to 80% among BPN-related deaths High-risk behaviours due to impaired memory, cognition & judgement Needle sharing Aggression intoxication link, criminality Poor performance (work, driving, parenting) Oliver and Keen 2003; Stenhouse and Grieve 2003; Ward &Barry, 2001; Grass et al, 2003, Kintz et.al.2002 Mikolaenko et al 2002; Wolf et al 2004; Ernst et al, 2002)

56 BZD-Comedication in ORT

57 Respiratory depression of Opiates + BZD Buprenorphine+Midazolam Buprenorphine Midazolam Gueye at.al. 2001

58 Risk of effect - enhancement Methadone and Buprenorphine alone are little respiratory depressive at steady-state conditions (CO2 +5 / +15 mmhg Methadone, -3 / +10 mmhg Buprenorphine). Similar findings for BZDs, TCAs, Neuroleptics, Zolpidem But: massive RD in combination + long half-life Walcher et.al. 1987, Nutt 2006, McCance-Katz 2006

59 Dependency and Tolerance Psychic Dependency: Urge to repeat the effect of a known substance, to continue using it (Cox `83) Irresistible need to repeat flush - ratio is knocked out (Wanke `88) Somatic Dependency: Urge to repeat the effect of a known substance, to relieve somatic suffering or discomfort (Brinkmann `94) Tolerance: Metabolic / cellular / neuroadaptive adaptation to substance effects (0.5-2x Alcohol up to > 80x Opiates/BZD). Crosstolerance (Alcohol, Nicotine, Opiates, Barbiturates, Narcotics). Cave: Loss of Tolerance => death after dismission

60 There s no simple way to safety

61 but there are some Conclusions: Therapy of drug-related Emergencies is simple, but it needs exercise and political willingness (eg. Drug-Checking, Naloxone-Programs) Overdose of Opiates (incl. ORT-medication) is the most common finding with a multitude of damages, responsible for more than 90% of DRD The common interaction with CYP-450 enzymes makes interactions between drugs and medications more complex Close relation to the clients and clinical observation of changes in (auto-)medication is most effective in prevention of DRD. Training of services and clients has proved to be effective.

62 Thank You CONCEPT center for addiction treatment Stephan Walcher

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