How do we manage the misuse of pregabalin? Pragmatic responses to a growing problem

Transcription

1 How do we manage the misuse of pregabalin? Pragmatic responses to a growing problem Graham Parsons Lead Pharmacist, Turning Point 20 th September 2017

2 What we will be covering Pharmacology & licenced uses Gabapentin vs. Pregabalin Why is pregabalin misused & in what doses? Evidence for misuse Prevalence of misuse DRDs & Pregabalin misuse Discontinuation Symptoms Managing dependent use & Harm Reduction Questions

3 Pharmacology Structural similarity to the neurotransmitter GABA Binds to alpha-2-delta subunit of the voltage dependent Ca channels in the CNS: glutamate, NA, substance P & calcitonin gene-related peptide PLUS produce GABA-mimetic properties Rapidly absorbed in fasted state with peak plasma concentrations within 1 hour Oral bioavailability 90 % Mean elimination t 1/2 of 6.3 hours Liner pharmacokinetics over recommended daily dose range Undergoes almost no metabolism largely excreted unchanged in the urine

4 Licensed uses Neuropathic pain (Dose: up to 600mg/day in 2-3 divided doses) NNT = 7.7 (for 50% pain relief) Postherpetic neuralgia (Dose: as above) Anxiety - GAD (Dose as above) Epilepsy (Dose as above) Other uses (unlicensed and/or international) include migraine, mania & bipolar disorder

5 Gabapentin vs. Pregabalin Similar mechanisms of action & effects Pregabalin characterised by higher potency (x2.5); quicker absorption rates & greater bioavailability vs. gabapentin (Schifano, 2014) Licensed doses higher vs. pregabalin (up to 4.8g/day in 3 divided doses for epilepsy) Mechanism for dependence? Unknown for the gabapentinoids as a group ( dopamine) Maximum reduction rate of 300mg every 4 days (PHE, 2014)

6 Why is pregabalin misused? Alcohol/GHB/benzodiazepine-like effects mixed with euphoria Dissociative effects Improved sociability, relaxation & a sense of calm Psychedelic effects Effects usually associated with higher doses & idiosyncratic (i.e. : IV, rectal, intranasal) drug intake modalities but mostly used orally (Schifano et al, 2014)

7 Why is pregabalin misused? Enhances the effects of heroin or may reduce its use (Lyndon et al, 2017) Enhances effect of alcohol & other prescribed/nonprescribed drugs including methadone (Schifano et al, 2014, BBC, 2017 & Lyndon et al, 2017) Effects reported between 10 minutes (i.e. quick acting) & 2 hours depending on route of administration Dependent and recreational use reported Rapid development & extinction of tolerance reported (DH, 2017)

8 An insight into Pregabalin misuse

9 What pregabalin doses are used for misuse purposes (Schifano et al, 2014)?

10 Evidence of pregabalin misuse: UK Numerous anecdotal reports Evidence in UK from secured settings high number prescribed (prescribing per capita x2 that in the community: PHE, 2014) that does not meet best practice guidelines (ACMD, 2016) TCAs rec as 1 st line DrugScope Street Drug Survey significant use chiefly among Britain s opioid-using and prison population (DrugScope, 2014) SPC states cases of abuse have been reported cautions in patients with HO substance abuse (& monitor for substance abuse) (emc, 2017),

11 MHRA Interactive Drug Analysis Profile (DAP) agency=mhra (accessed 17/09/2017)

12 Evidence of pregabalin misuse: International Finland (1): Study of toxicology reports of DRDs between suggest a substantial increase in DRDs involving pregabalin & opioids (Lyndon et al, 2017) Finland (2): In same study opioids present in 90% of deaths involving pregabalin/gabapentin & incidence of pregabalin misuse in DRDs was >7x vs. gabapentin USA: Placed under control in 2005 by DEA citing abuse which may lead to limited physical dependence or psychological dependence (ACMD, 2016) Germany: Reported since 2008 with increasing frequency to the German medical regulatory body

13 Prevalence of pregabalin misuse International SR (2017 n=59) indicates 1.6% prevalence of gabapentinoid abuse ; to 3% to 68% among opioid abusers. Risk factors for misuse included a H/O substance abuse (particularly opioids) & psychiatric comorbidities (Evoy et al, 2017) International SR (2016 n=33) indicates 1.1% prevalence of gabapentin misuse in general population ; to 15% to 22% within opioid abuse samples (Smith et al, 2016)

14 DRDs & Pregabalin misuse Depresses CNS drowsiness, respiratory depression, failure & death (especially when there is poly-drug use) Deaths where pregabalin/gabapentin were mentioned on death certificates (in E&W) from fewer than 1/year before 2009 to 137 deaths in 2015 (Lydon et al, 2017) In 79% of these deaths, opioids were mentioned Increase in deaths was correlated highly with prescribing data (correlation coefficient 0.94) In animal models S-pregabalin produced profound depression of respiration within 5 minutes which was maintained for 30 minutes not prevented by naloxone effects of morphine & pregabalin summate Pregabalin may reverse morphine tolerance (Lyndon et al, 2017)

15 Lyndon et al, 2017

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17 Discontinuation Symptoms of Pregabalin Insomnia (5.2% in long-term [6m] clinical trials) Headache (3.2%) Nausea & dizziness (4.0% for nausea) Anxiety, nervousness, depression Diarrhoea (2.8%), flu syndrome, pain & hyperhidrosis Convulsions may occur shortly after discontinuing Incidence and severity of withdrawal symptoms may be dose-related (emc, 2017)

18 How can dependent use be managed? Insufficient evidence to guide practitioners SPCs suggest discontinue over a week (However, is to minimise the risk of increased seizure frequency where they are being used for patients with seizure disorders) PHE suggest a more gradual reduction to reduce Symptoms Maximum reduction rate of mg/week for pregabalin Insufficient evidence regarding use of substitute/adjunctive medications PSIs

19 Harm Reduction for service users misusing pregabalin Caution re prescribing in Primary Care Risk & comprehensive assessment Use of alternatives (when appropriate) Daily (or less frequent than 28/56 day) prescribing PSIs Naloxone distribution Oral vs. IV Poly-drug use Scheduling soon? Class C & Schedule 3

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21 References Evoy K.E et al (2017) Abuse and Misuse of Pregabalin and Gabapentin. Drugs 77:4 pp Lyndon A et al (2017) Risk to heroin users of polydrug use of pregabalin or gabapentin. Addiction 112:9 pp emc (2017) Lyrica Capsules 25mg,50mg,75mg,100mg,150mg,200mg,225mg and 300mg (Last Updated on 14-Jul-2017) Smith R.V et al (2016) Gabapentin misuse, abuse and diversion: a systematic review. Addiction 111:7 pp Clinical Guidelines on Drug Misuse and Dependence Update 2017 Independent Expert Working Group (2017) Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health PHE (2014) Pregabalin and gabapentin: advice for prescribers on the risk of misuse ACMD (2016) Pregabalin and Gabapentin advice Schifano F et al (2014) Is there a recreational potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data BBC (2017) Inside Out South West 11/09/2017 An investigation into the illegal trade in prescription painkillers in the south west Drugscope (2014) DrugScope Street Drug Survey

22 Blood tests and liver disease Amanda Clements Hepatology Advanced Nurse Practitioner, South West Liver Unit Derriford Hospital Plymouth

23 Who am I? And so what?

24 Understanding blood (LFTS) tests Very commonly requested Common to see abnormal LFTs raised ALT Not all of the results reflect Liver Function lets start with Understanding the basics of the liver anatomy What the healthy liver does What happens to a damaged liver Common LFT abnormalities and their significance Looking at blood tests that diagnose liver disease

25 Is that OK? What would like to cover? Ask questions

26 Anatomy Largest solid organ (after skin) kg 2.5% body weight Under the rib cage Right upper quadrant of the abdomen

27 embryology 4 th week development 12 th week liver begins to secrete bile late pregnancy liver 5% of weight

28 Anatomical variant Reidel lobe extension of right lobe liver

29 Gross anatomy Divided by falciform ligament (remnant of embryonic umbilical vein) FL Attaches Liver to diaphragm and ant. abdo. wall Fibrous Glisson s Capsule

30 Segmental Anatomy (Couinaud System) Caudate Lobe Segment I Left Lobe Segments II IV Right Lobe Segments V-VIII

31 Liver Vasculature ¼ of resting cardiac output normal cardiac output pumps about 5-6Lblood/min at rest Liver dual blood supply Hepatic artery oxygenated blood Hepatic portal vein deoxygenated bloodnutrients, drugs, toxins etc from GI tract

32 Liver drainage 3 major veinsleft, middle, right hepatic veins Into inferior vena cava

33 Biliary drainage Gallbladder under R lobe Stores / concentrates bile Drained by cystic duct, joins common hepatic duct to form common bile duct

34 Microscopic anatomy - lobule Functional units, Hexagonal structure Organised around central vein (tributary of HV) portal triad /tract = branches of HA, PV, BD - form corner of hexagon

35 Microscopic anatomy - acinus Liver parenchyma in zones Hepatocytes Zone 1 closes to portal triad = richest supply of O 2 & nutrients, more likely to be damaged by drugs / toxins Zone 3 nearer central vein poor O 2 = hypoxic damage

36 Bile formation & excretion Bile = water, electrolytes, bile pigments, bile acids, cholesterol, phospholipids, albumin, immunoglobulins Lipid digestion & absorption, immunological defence, excretion of endogenous compounds, removal of xenobiotics mg produced a day Bile secreted by hepatocytes, flows into bile canniculi small bile ducts R&L hepatic ducts that unite, leave liver as CBD

37 Sinusoids Spaces lines with endothelium, partly lined with stellate reticulo-endothelial Kuppfer cells Particle eating macrophages / phagocytes break down old red/ white blood cells, bacteria, foreign matter Hepatic lymph formed by drainage of perisinusoidal space of Disse drain into portal vessels

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39 Now compare to Cirrhotic Histology

40 Functions of the liver Over 500! Main functions Detoxification of blood from the Gut Production of bile Synthesis Proteins esp Albumin Clotting factors Glucose Bile synthesis Breakdown Carbohydrates Haem Drugs Alcohol Storage Vitamins/minerals

41 Synthesis Key role in carbohydrate, protein and lipid metabolism Proteins Clotting factors Albumin - maintenance of oncotic pressure, Amino acid synthesis Carbohydrate Glycogen synthesis Gluconeogensis Lipids cholesterol, lipogenesis, triglycerides + lipoproteins Bile production

42 Breakdown Proteins Breakdown of amino acids Waste products From GI tract via portal vein ie Ammonia = converted into urea Drugs Nearly all drugs are metabolised in the liver Toxic substances Alcohol Bilirubin Breakdown and excreted in bile via enzymatic process Lack of enzyme = Gilberts

43 Drug metabolism Metabolism = enzymatic conversion of one chemical compound into another. Occurs in hepatocytes via cytochrome p450 group Metabolism divided into two phases phase 1+ phase 2. > 50 CYP450 enzymes Many factors can effect liver drug metabolism. Genetics CYP450 inducers and inhibitors = foods + drugs Elderly population = less hepatocytes + less enzyme activity Reduced hepatic blood flow ie heart failure/ shock = reduced metabolism

44 Drug factors for the wards Grapefruit and statin Cranberry and warfarin Seville oranges and Tacrolimus St Johns Wort inhibits cp450 Smoke and brussel sprouts increases cp450 activity.

45 DILI Drug induced liver injury >1,000 drugs/herbs/otc can cause DILI Commonest cause of ALF Most frequently reason for drug withdrawal DILI may not be detected prior to drug approval, most new drugs are tested in < 3000 people prior to drug approval. Therefore cases of DILI with an incidence of 1 in 10,000 may be missed. Diagnosis Resolves on drug withdrawal Rule out all other causes Assess causality Common causes Augmentin, Flucloxacilliin Paracetomol NSAIDs

46 Paracetamol overdose (POD) Commonest agent used in self harm 150 deaths each year from it Treat with NAC Based on paracetamol levels If in doubt treat Weight based 1 hr, 4 hr and 16 hr bag Monitor closely BD bloods Abx and antifungals if temp

47 Storage Stores multiple vitamins, minerals and glucose Glucose Stored as glycogen Used as quick release of energy Check glucose levels in all pts with liver disease Vitamin A (1 2 years' supply) Vitamin D (1 4 months' supply) Vitamin B12 (3 5 years' supply) Iron and copper

48 Distortion of Liver architecture can lead impairment of liver function What happens to liver tissue?

49 GOOD BAD UGLY Normal Steatotic Cirrhotic 28

50 Factors that change with liver damage: Impaired control of blood glucose Lack of storage of vitamins and minerals Vit A = vision, skin health Vit D bone strength risk of osteopaenia/porosis Vit B / B12 brain and Nervous system function Iron Copper Reduced processing of lipids Energy levels, hormone production, cell membranes / cell repiar, reduced cholesterol Inability to detoxify drugs, alcohol, chemicals (NH3) Build up of toxic substances confusion memory encephalopathy

51 Factors that change with liver damage: Bile secretion impaired / inability to break down RBC Affects digestion of fat Reduced absorption of fat soluble vits ADEK Jaundice Pruritus steatorrhea Lack of clotting factors + vit K Coagulopathy bruise / bleed easily Splenomegaly thrombocytopaenia Disrupted blood flow Flow of blood from gut restricted = back pressure Portal hypertension Enlarged blood vessels OV GV rectal V Variceal bleeding

52 Factors that change with liver damage: Inability to maintain intravascular fluid balance Low ALBUMIN oncotic pressure lost oedema, ascites Reduction in transport of drugs, hormones, minerals etc Inability to fight infection Imune defence system impaired more susceptible to infection

53 Some of the commonest aetiologies of liver disease Infection Viral hepatitis's Immune system abnormalities AIH PBC PSC Toxins Alcohol / drugs DILI Metabolic NASH Genetics Wilson s GHC Congenital Biliary atresia Venous changes Budd Chiari PVT

54 Signs Palmer Erythema Spider Naevi

55 Signs Cachexia Jaundice

56 ASCITES

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59 Biochemical markers of parenchymal liver injury ALT alanine aminotransferease Liver specific, in cytoplasm Half life 47 hours Elevated values acute hepatitis, DILI, AST Aspartate aminotransferase Non-specific also elevated in MI, Musculo-skeletal, Elevated in acute hepatitis, alcohol related damage Half life 17 hours Alk phos Alkaline Phosphatase Not liver specific bone, kidney, intestine, placenta Elevated in cholestasis, hepatic infiltration, slight increase in hepatitis and DILI Half life 1-7 days ggt-gamma-glutamyl transferase Liver specific Elevated in biliary cholestasis, toxic damage / alcohol

60 Biochemical markers of parenchymal liver injury Synthetic function Bilirubin Indirect / direct Conjugated / unconjugated Metabolite of haem Elevated over 50 jaundice Albumin Half life 20 days Good marker of liver function Nutritional status / malnutrition Renal disease Severe burns pregnancy Clotting time PT Prothrombin time Prolonged PT deficiency Factors VII X V II Vit K deficiency Consider anit-coagulants Platelets Thrombocyopaenia splenomegaly Hb haemoglobin Wcc white cell count / CRP Infection Renal function

61 Lets look at some examples.

62 Cholestasis

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64 Alcoholic Hepatitis

65 ARLD cirrhosis

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71 Virology HIV Ab HAV HBV Acute / chronic infection HCV Ab HCV RNA PCR Viral quantitation What do you do with a positive result?

72 End of Life Care for Clients with Substance Misuse Issues Gilly Barringer Gilly Barringer

73 The Surprise Question Ask yourself Would you be surprised if the person was to die in the next 6-12 months?

74 3 rd Trigger - Prognostic Indicator Guide

75 Cancer

76 Frailty

77 Organ Failure

78 What are the challenges for caring for this client group?

79 >>AVOID TEXT IN THIS AREA<< CHALLENGES Chaotic Population Difficulty predicting illness trajectories Need for Holistic approach to care and support Professional reluctance to discuss advance care planning Lack of co-ordination of care/lack of continuity Boundaries between social and health care Need for more pro active discussion about End of life/advanced care planning issues.

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81 Advance Care Planning why bother?

82 Thank you for Listening