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Structure • • • • • • Epidemiology /Context Deaths from methadone Metabolism and risks with other drugs Respiratory depression with opioids Hepatitis C Cardiac problems Numbers of opiate users /OCU by age group Cumbria (2011-2012 estimates) Opiate OCU 15-24 223 243 25-34 1,183 1,433 35-64 1,271 1,262 Centre for Public Health, Liverpool John Moores University (Hay, 2014) Rate per 1000 estimate of opiate users by age group (2011-2012 estimates) 15-24 Cumbria 4.00 Manchester 2.63 North West 2.58 ENGLAND 3.60 25-34 16.84 11.58 13.25 13.35 35-64 6.00 17.64 9.91 6.48 In Unity, for those prescribed Mean =40 SD =8, normal distribution Rates per 1000 estimate of drug users 15-64 population (2011-2012 estimates) OCU Opiate Crack Cumbria 7.48 7.40 1.35 Manchester 12.97 11.65 9.46 North West 9.99 9.07 5.47 ENGLAND 8.40 7.32 4.76 Injecting 3.59 4.12 2.83 2.49 Cost drug use UK Focal Point On Drugs Annual Report to the European Monitoring Centre for Drugs and Drug Addiction Clients (n=4817 ) aged 11–65 years who sought treatment for drug use (Helsinki) Primary Drug Alive (n= 4321) Alive % Dead (n= 496) Dead % Total (n= 4817) Total % Dead/ Total % Alcohol 930 22 74 15 1004 21 7.4 Cannabis Prescriptio n medicines 825 19 69 14 894 19 7.7 79 2 17 3 96 2 18 Opiates 1290 30 142 29* 1432 30 9.9** Stimulants 1146 27 188 38 1334 28 14 51 1 6 1 57 1 11 Others * For example 142/496 *100 = 29 ** For example 142/1432 *100 = 9.9 Onyeka,2014 Deaths for people who sought who sought treatment for drug use Causes of death All All deaths deaths (n = 496) % Disease Neoplasms Mental Circulatory Deaths external Transport Accidental poisioning/OD Suicide Assault 25–34 25–34 years years (n = 189) % 35–44 35–44 years years (n = 107) % ≥45 years ≥45 years (n = 78) % 38 3 9 11 35.5 2.8 8.4 10.3 53 11 4 18 67.9 14.1 5.1 23.1 174 15 49 45 35.1 3 9.9 9.1 53 19 14 28 0.5 10.1 7.4 322 16 64.9 3.2 136 6 72 3.2 69 3 64.5 2.8 25 2 32.1 2.6 165 108 14 33.3 21.8 2.8 66 52 6 34.9 27.5 3.2 42 16 3 39.3 15 2.8 12 8 15.4 10.3 1 Onyeka,2014 Causes of death in people with opioid dependence in NSW 1985–2006 < 25* Accidental opioid-related Accidental other drug-related Suicide Liver-related Cardiovascular Cancer HIV Motor vehicle accidents Violence Other *age of death <25 % 25-34 25-34 % 35-44 35-44 % >45 >45 % 209 59.5 699 50.9 542 40.9 124 20.3 14 53 1 2 3 6 4 15.1 0.3 0.6 0.9 1.7 71 211 23 38 17 37 5.2 15.4 1.7 2.8 1.2 2.7 56 167 124 82 90 33 4.2 12.6 9.4 6.2 6.8 2.5 23 53 106 84 80 15 3.8 8.7 17.3 13.7 13.1 2.5 26 11 26 7.4 3.1 0 96 37 144 7 2.7 10.5 42 31 157 3.2 2.3 11.9 16 6 105 2.6 1 17.2 Degenhardt 2013 SMR in people with opioid dependence in NSW 1985–2006 Causes of death SMR Total mortality 6.5 All drug-related 35 Accidental drug-related 39.9 Accidental opioid-related 42.8 Accidental other drug-related 24.1 Unintentional injuries 9.6 Motor vehicle accidents 3.2 Violence 7.6 Suicide 6.2 CI (6.3–6.7) (33.4–36.6) (38.0–41.8) (40.7–45.0) (20.6–28.1) (9.0–10.2) (2.7–3.7) (6.1–9.5) (5.6–6.7) SMR in people with opioid dependence in NSW 1985–2006 Causes of death All liver-related Chronic liver disease Viral hepatitis Cardiovascular Cancer HIV AIDS Alcohol-related Chronic respiratory disease Respiratory infections SMR 11.4 6.5 46.3 2.1 1.7 4.4 5.4 3.9 7.9 CI (10.1–12.9) (5.3–8.0) (38.5–55.2) (1.9–2.5) (1.4–1.9) (3.5–5.3) (4.4–6.6) (2.7–5.5) (5.1–11.8) Trends in deaths 3500 1000 900 3000 800 700 Drug Related deaths Methadone 600 2500 2000 400 Drug Related deaths Buprenorphine 1500 300 Heroin and Morphine 1000 500 Drug Related deaths Methadone All Drug related Deaths 200 500 2012 2011 2010 2009 2008 2007 2006 2005 0 2004 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 0 2003 100 ONS 2014 Metabolism review • Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. It involves the cytochrome P450 (CYP) enzymes • Phase 2 metabolism conjugates the drug to hydrophilic substances, such as glucuronic acid, sulfate, glycine, or glutathione. • The most important phase 2 reaction is glucuronidation • Glucuronidation produces molecules that are highly hydrophilic and therefore easily excreted. First Pass Effect Medcape First pass effects • Enzymes for phase 1 metabolism are mainly found in the GI tract (liver, small intestine, and colon). • High concentration enzymes in GI epithelium, hence this is the initial site for first-pass metabolism of drugs. • The drug via portal circulation goes to the liver, • Some active drug may miss first-pass metabolism in the GI tract and liver but subsequent passes through the liver result in further metabolism of the parent drug until it is eliminated • Nasal mucosa and lung also have these enzymes for first pass. important roles in the first pass metabolism of airborne pollutants and aerosols. Goodman Metabolism Metabolism of opioids • The basal rate of metabolism is determined by genetic makeup, gender, age, as well as environment including diet, disease state, and concurrent use of medications. • Most opioids are metabolized by glucuronidation or by the P450 (CYP) system. • Polymorphism in the human OPRM1 gene (encodes the mu opioid peptide (MOP) receptor) may relate to variation in opioid sensitivity – E.g., opioid analgesia, tolerance, and dependence Smith 2009 Metabolism of opioids • The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone, codeine, and dihydrocodeine to their active metabolites which in turn undergo phase 2 glucuronidation. • These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with an array of other drugs which are substrates, inducers, or inhibitors of the CYP2D6 enzyme • Morphine, oxymorphone, and hydromorphone metabolized by phase 2 glucuronidationand therefore have little potential for metabolically based drug interactions. Smith 2009 Interactions • http://bioinformatics.charite.de/supercyp/ind ex.php?site=get_drug_interaction • Nicotine also important to consider Methadone • Methadone plasma concentrations follows a biexponential 1. rapid phase- transfer of the drug from the central compartment to the tissue compartment 2. slow phase - corresponds to elimination • The t1/2 of the first phase of methadone varies from 1.9 to 4.2 h • The t1/2 of the second phase (slow) of drug disappearance from the plasma (-phase, slow, elimination) varies even more, from 8.5 to 47 h Ferrari 2004 Methadone • High lipid solubility, hence rapidly transferred to tissues, particularly liver, kidneys, lungs and to the brain • 1–2% remains in the blood compartment • 60–90% bound to plasma proteins, mostly to acid 1globulins • The blood concentrations of acid 1-glycoproteins, increase in stress conditions and in heroin dependent users with a decrease of free and active methadone • Large Volume of distribution of methadone - short term decreases in blood levels not clinically important Ferrari 2004 Methadone variability • Induction of its own metabolism may reduces methadone concentrations • Different views about extent of this 1. 30 days treatment of 40 or 80 mg, 1. Decrease plasma level by three to eight-times 2. Excretion of parent drug and metabolites increase from 22.2 to 61.9%. 2. 5–12 months of treatment with 60 or 80 mg 1. Decrease plasma level by 15–25% • Body clearance of methadone varies from 0.96 to 6.1 ml/min/kg Ferrari 2004 Opioid pharmacology Mu Delta Kappa Mu 1 – Analgesia Mu 2 – Sedation, vomiting, respiratory depression, pruritus, euphoria, anorexia, urinary retention, physical dependence Analgesia, spinal analgesia Analgesia, sedation, dyspnea, psychomimetic effects, miosis, respiratory depression, euphoria,dysphoria, dyspnea k agonist Actions of opioids Drug Mu Morphine Agonist Codeine Weak agonist Fentanyl Agonist Methadone Agonist Buprenorphine Partial agonist Delta Kappa Weak agonist Weak agonist Partial agonist Opioid induced respiratory depression case reports • 34 case reports describing OIRD in 42 adolescent and adult patients treated for chronic cancer and non-cancer pain from 1980 to 2012. • The number of cases is relatively small compared to OIRD in acute pain patients (120 cases), but there is a substantial increase in the incidence of cases post-2000 (pre-2000: 0.8 cases/year versus post-2000: 2.3 cases/ year). Dahan 2013 15 cases 1980- 2000 27 cases 2000 - 2013 Indication cancer pain 67% pre-2000, 41% post- 2000 Dahan 2013 Reason long term opioid used • The indication for opioid use was cancer pain in 67% of the cases pre-2000, but dropped to 41% post- 2000 • Post-2000 the indication for opioid prescriptions for non-cancer pain was 59%, most commonly for treatment of musculoskeletal pain (33%) followed by neuropathic pain and complex regional pain syndrome (11%) Age/ Sex Length Complication 42 yr. F Methadone 6 years Sedation/respira Ciprofloxacin Inhibition of tory CYP1A2 and 3A4 depression activity, responsive to increasing naloxone methadone blood levels Methadone 15 days Respiratory depression responsive to naloxone 60 yr. M Drug Other Drugs Cause Fluconazole Inhibition of CYP3A4 and 2Y9, increasing methadone blood levels Dahan 2013 Age/ Sex Drug 46 Fentanyl TD yr. M patch morphine, oxazepam Length Complication 45 days 8 days following start of fluconazole patient died during sleep. Forensic analysis showed high plasma conc. of fentanyl and fluconazole 34 Buprenorphine 12 h yr. M TD patch Respiratory depression upon start of chemotherapy with ifosfamide resolved by removal of the patch Other Drugs Cause Fluconazole Inhibition of CYP3A4 system, increasing fentanyl blood levels Ifosfamide, an alkylating agent Possible competitive interaction via common metabolic pathway (CYP3A4 Age/ Drug Sex 81 yr Fentanyl TD M patch 46 yr Methadone M Length Complication Longterm 36 h after receiving the first dose of clarithromycine he developed naloxoneresponsive respiratory depression. 4 Smoking cessation months (after 33 pack years) initiated naloxoneresponsive respiratory depression Other Cause Drugs Clarithrom Inhibition of the ycin CYP3A4 system, increasing fentanyl’s plasma levels Smoking cessation Polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2. Smoking cessation may have reduced methadone’s metabolism. Age/ Sex Drug 70 yr. M 61 yr F Length Complication Other Drugs Cause Methadone Event 1 week after long term opioid use Respiratory depression responsive to naloxone Sertraline Inhibition of the CYP system, increasing methadone blood levels. Methadone Long-term Naloxoneresponsive respiratory depression 11 days after carbamazepine withdrawal Carbamaze pine Gabapentin Induction of CYP3A4 activity. Its withdrawal slows down methadone’s metabolism causing an increase in plasma levels Hepatitis C • In England, 160,000 adults are estimated to be chronically infected with hepatitis C • This is about 0.4% of the adult population. • Injecting drug use continues to be the most important risk factor for HCV infection • In England, 16% of PWID reported direct sharing of needles in 2013 (29% in 2003). PHE 2014 Deaths from ESLD or HCC in those with HCV mentioned on their death certificate in England: 1996-2013** Risk factor information in laboratory reports* of hepatitis C from England: 1996-2013 Number of deaths from ESLD* or HCC in those with HCV mentioned on their death certificate by PHE Centre 2008-2013** (per 100,000 population) Unlinked Anonymous Monitoring Survey of Hepatitis C* in PWID 80% 70% *Proportion of samples antiHCV positive 60% 50% 40% England 30% North West 20% 10% 0% Factors for QTc • Methadone prolongs QTc in a dose dependent manner • QT prolongation is used as the surrogate marker for TdP • If methadone is a risk factor why does not everyone suffer from QTc elongation on methadone? • “Forme fruste” theory • Certain people at risk for QTc elongation but need trigger for it to occur Risk factors of QTc • Metabolic disorders/ Misc • hypokalemia, hypomagnesemia, hypocalcemia • Starvation • Anorexia nervosa • Hypothyroidism • HIV infection • Hypothermia • Connective tissue disorders with anti-Ro/SSA antibodies • Male, age • Cardiac disease • Bradyarrhythmias: sinus node dysfunction, AV blocksecond or third degree • Advanced cardiac disease • Myocardial ischemia or infarction, esp. with prominent T wave inversions Mujtaba, 2013 Drug Causes of QTc • Antiarrhythmic drugs e.g.: quinidine, procainamide, sotalol • Antimicrobial drugs: erythromycin, azithromycin, levofloxacin • Antihistamines: terfenadine • HIV Protease inhibitors: ritonavir, nelfinavir, atazanavir • Psychotropic drugs: thioridazine, haloperidol, olanzapine • Motility drugs: cisapride, domperidone http:// www.azcert.org/medical-pros/drug-lists/drug-lists.cfm, www.qtdrugs.org. Myocardial action potential Phases K efflux Na entry K re-enters Na exits Slow Ca entry K exit cause 2 Gupta 2007 QTc prolongation • Myocardial repolarization via efflux of potassium ions. • Mediated by two subtypes of the delayed rectifier K+ current, Ikr (rapid) and Iks (slow) • Drugs prolonging QTc block Ikr thereby delaying phase 3 • Longer action potential results in QT prolongation. – It may also distort T waves or produce prominent U waves Gupta 2007 Mechanism of action • Inhibitor of Ikr • Increased QT dispersion (marker of heterogenous cardiac repolarization) has been observed in association with methadone • Methadone has bradycardia effect – Due to anticholinesterase & calcium channel antagonist properties – Adds to risks TdP Mujtaba, 2013 Comparison of opioids effects on Ikr IC50 for HERG Maximum Plasma Drug Blockade (uM) Conc. (Cmax) (uM) Ratio: IC50/Cmax Methadone 9.8 3.6 2.7 Fentanyl 1.8 0.030 60 Buprenorphine 7.5 0.036 208 Morphine >1000 2.5 >400 Codeine >300 0.66 >455 Katchman 2002 Electrical impulse http://en.wikiversity.org/wiki/User:Bron766/E CG/Axis http://courses.kcumb.edu/physio/ecg%20prim er/ecgaxis.htm Normal ECG http://www.ecglibrary.com/ecghome.html Torsade de pointes Patients with opioid dependence in Taiwan • Taiwan launched MMT in 2006 in response to the HIV/AIDS surge endemic in eastern Asia • 33,603 patients registered throughout 2006 to 2008 • Average age = 37.7 years, men (84.8%), • HIV infection rate was 14.1% • The average treatment duration was 171.5 days, and the average follow-up duration 358.4 days. • Mean (SD) methadone dosage was 46.5 (20.9) mg/day. • No take-home dosage was permitted throughout the treatment Adjusted hazard ratios for all-cause deaths for MMT patients 2006 -08. Age ≤30 Adjusteed hazard rate CI for adjusted hazard rate P for trend 1 1 30-45 0.96 (0.74-1.25) 0.767 45-60 0.75 (0.56-1.01) 0.057 >60 0.68 (0.50-0.92) 0.016 Adjusted for age, sex, marital status, education, HIV status Hazard function of low to high methadone dosage subgroups Ding-Lieh Liao 2013 Comparison 1 RCT, Outcome 6 Opioid abstinence at >3-4 weeks (urine based). Faggiano 2003 MMT vs No MMT Morphine positive urine or hair analysis. Mattick 2009 High-dose buprenorphine versus placebo, Morphine-positive urines Treatment opioid dependence • The needs of all drug misusers should be assessed across the four domains of drug and alcohol misuse, health, social functioning and criminal involvement. • Risks to dependent children should be assessed for all drug-using parents. • All drug misusers entering structured treatment should have a care or treatment plan which is regularly reviewed. • A named individual should manage and deliver aspects of the patient’s care or treatment plan • Drug testing can be a useful tool in assessment and in monitoring • Drug misuse treatment involves a range of interventions, not just prescribing. DOH 2007 Pharmacological components • Methadone or buprenorphine are are effective medicines for maintenance (opioids) • Dose induction with buprenorphine may be carried out more rapidly with less risk of overdose • Care with children • Supervised consumption should be available • Methadone, buprenorphine, lofexidine are effective in detoxification regimens DoH 2009 Drug misuse and dependence. UK guidelines on clinical management Opioid substitution treatment (OST) effectiveness • The evidence is good that OST – OST reduces the risk of death among heroin users participating in treatment – Suppresses illicit use of heroin – Prevents people dropping out of treatment reduces crime – OST reduces involvement in crime among heroin users participating in treatment – OST reduces the risk of BBV transmission, including in prisons Medications In Recovery Re-orientating Drug Dependence Treatment NTA 2012 Opioid substitution treatment (OST) effectiveness • Evidence is less good that OST – Suppresses other drug use – Promotes abstinence from all drugs – Improves physical and mental health –the evidence suggests rapid and substantial improvements on treatment entry, which may or may not be maintained or further improved – Improves social reintegration of marginalised heroin users Medications In Recovery Re-orientating Drug Dependence Treatment NTA 2012