Opiates and Opioids

Opiates – naturally occurring compounds in the opium poppy that attach to opioid receptors Opioids – Compounds which attach to opioid receptors (includes naturally occurring and (semi)synthetic

• Natural opiates are those in the poppy • Semi-synthetic use poppy opiates as precursors- just have additional groups attached • Synthetic – other molecular precursors; these are very structurally different to the natural opiates

**‘Weak’ and ‘strong’ **– potency, not concentration (pharmacological affinity and efficacy)

Gi/o is the protein receptor that opioids bind to A GPCR- inhibits cAMP formation

Enkephalins and endorphins are opioid receptor agonists, and their activity is very much dependent on receptor mediation • Endorphins thought to mediate response to pain in certain situations. Injection in a dark alley probably hurt more than injection for flu vaccine because endogenous endorphins damped pain response in a ‘flu vaccine’ setting • Endogenous endorphins and enkephalins aren’t as strong as those we can take recreationally

• Heroin (opiate) • Morphine (opiate) • Codeine (opiate) • Fentanyl (opioid) • Oxycodone • Methadone • …. • Tramadol (also an SSRI, selective serotonin reuptake inhibitor as well an exogenous agonist)

• Can be **smoked or injected ** • Heroin is more commonly smoked than injected. Reasons for smoking • *First time users scared of injecting • *No accessible veins • *Testing a new batch of heroin for potency • Injecting gives a more intense ‘high’

Rapidly metabolised to 6-acetylmornine (6-MAM) and morphine

t1/2 Heroin= 6 minutes t1/2 6-MAM= 30 minutes Hence why in OD you ‘never see heroin’

• Heroin markers: 6-MAM, contaminants when opium poppy is grown it is distilled to get the heroin but sometimes there are other opiates present (Noscapine, papaverine, thebaine)

• Heroin markers: • 6-MAM present (therapeutic and illicit) • Contaminants present (Noscapine, papaverine, thebaine) (illicit) • Morphine • Metabolised to other components (morphine-3-glucuronide and morphine-6-glucuronide) • No 6-MAM present in morphine OD so use this to distinguish if used has taken heroin or morphine • No contaminants • Codeine • Converted to morphine via enzyme (this enzyme is variable and can effect rate of conversion) • Codeine is an opioid but not as potent as morphine, high analgesic effect if have fast metaboliser for codeine • No 6-MAM • morphine ≤ Codeine (as codeine is metabolised to morphine so morphine will be present if codeine taken but at a lower amount)

• Fentanyl 50-100x more potent than morphine • Carfentanyl 10,000x more potent • Carfentanyl marketed as Wildnil for darting rhinos etc. • Use to adulterate heroin, make it ‘stronger’ • Even having carfentanyl in the air can be fatal

Fentanyl, remifentanyl, sufentanyl, alfentanyl

Carfentanyl, ocfentanyl, butyrylfentanyl

• Massive spike in 2017 when pharmaceutical fentanyl was detected with NPFD, and this came from heroin that was mixed with carfentanyl. This lab supplying this shut down which lessened the rate and the people who took that drug and had heard about deaths didn’t want to use the drug (LHS graph) • Just deaths with fentanyl shows illicitly precured fentanyl. Problem with prescriptions being misused and those illicitly sourcing for recreational purposes. (RHS graph)

o Analgesia o Cough suppression (methadone can be prescribed in people with lung cancer as good cough suppressant and pain relief) o Euphoria- big reason why used recreationally o *Antidiarrheal action

o Respiratory depression o Nausea/vomiting o Pupillary constriction o Dependence o Histamine release- causes user to scratch them self in withdrawal as causes mast cell degeneration/degranulation in periphery and releases histamine which causes skin itching  Non-drowsy (allergy) and drowsy (crosses BBB, if take with heroin then will inhibit mast cell degranulation, and will provide some sedation, but can cause loss of consciousness, respiratory depression and death) o *Antidiarrheal action

• Aggressive marketing campaign –> Targeted doctors who had large chronic pain patient rosters • ‘Risk of addiction is less than 1%*’- what doctors were told when being marketed Oxycontin, however was addictive o The study where this 1% figure was from was about burns patients who received limited doses • Increased dependence with this in the US in particular “paving the way for the current fentanyl crisis”- >90% of deaths in <50 due to fentanyl

• Tolerance: if taken drug your body adapts, and you don’t feel the same effects so take a higher dose. These keeps occurring until there’s a cross over between therapeutic effects wanted and respiratory depression • If relapse and start to use at same level which you stop using, then could be a fatal dose as you have lost the tolerance you initially had

* Antagonists o Naloxone- high affinity for opioid receptor, competitively antagonise and stops opioids binding, this is quick o Naltrexone * Opioid substitution therapy- chronic users o Methadone- full agonist but not as potent o Buprenorphine- High affinity, low efficacy

• Can die very quickly so getting naloxone to people quickly is key to save lives • Doing a case in Plymouth

* Case scenario: o Heroin user reports to A&E o Classic signs of opioid toxicity o What are they?  Losing consciousness  Struggling to breath  Pupillary effect o Given naloxone o Woke up and became agitated o Restrained and put in cubicle o Seemed to settle (no more shouting, not ‘seen’ for an hour) o Found lifeless o Why?  Naloxone has a short half-life  So reversed that part of opioid experience  So naloxone has been metabolised and could be high opioid levels in body • Half-life of naloxone 1-1.5hrs. Heroin 4-6 hours. Naloxone can be metabolised whilst still in the window for heroin overdose

• Still an opioid (i.e., addictive) • ‘Weaker’ than heroin • Long duration of action (24-36hrs vs 4-6hrs for heroin) • No euphoria • Daily supervised dosing (then take home)- do daily supervised before take home to ensure they aren’t supplying or taking more than recommended dose