Lecture 10 - Opioids 2 Flashcards
What are opioids?
Most potent painkiller at the moment
What is pain?
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
What is nocioception?
The neural process of encoding noxious stimuli, i.e. stimuli causing tissue damage (can have no observable tissue damage and still perceive chronic pain)
What is chronic pain?
Pain that lasts or recurs for longer than 3 months; can be symptom or disease in itself, i.e. with no clear relation to tissue damage. Affects about 20% of people worldwide (Treede et al., 2019)
What is the relationship between pain and nociception?
Pain can appear without nociception
How is pain related to disability in the UK?
Pain is the leading cause of disability in the UK – years lived with disability (YLD) = low back and neck pain in males and females longest lived with
Describe the ascending pain pathway
- PSNs receive info from periphery through the spinal cord and brain stem, then activate cortical areas leading to the conscious experience of pain
- PSN in DRG -> neuron in dorsal horn of spinal cord -> thalamus -> cortex
- ‘First/fast’ pain:
- PSNs with Adelta fibres -> somatosensory cortex
- ‘Second/slow/late’ pain:
- PSNs with C fibres -> other cortical and subcortical areas
Describe the descending pain pathway
- Goes out from CNS to PNS and modulates our experience of pain
- Cortical areas modulate this pathway
- Descending pathways originate in midbrain regions, including periaqueductal grey, and INHIBIT pain processing
How do opioids inhibit pain processing?
- Opioids disinhibit a descending pain pathway that inhibits pain
- Opioids inhibit the ascending pain pathway
- These mechanisms only apply to acute pain (different mechanisms underlie chronic pain)
How are opioids related to acute vs chronic pain?
- Opioids inhibit acute pain, but there is limited evidence that they inhibit chronic pain
- ‘High-dose opioids for chronic non-cancer pain: an overview of Cochrane reviews’ – Els et al. (2017)
- There is no high‐quality evidence to show how well high doses of opioids work, or what side effects there are when these medications are used for the treatment of chronic pain that is not due to cancer in adults
Meso-corticolimbic dopamine system and reward
- Drive people to want opioids
- Increases of dopamine in nucleus accumbens key to how rewards are processed in the brain
- Opioids in VTA increase release of dopamine
How may opioids increase dopamine release within the nucleus accumbens?
- Disinhibition of dopaminergic neurons in the VTA: opioids stimulate opioid receptors of GABA neurons, inhibiting GABA release by these neurons, thereby allowing an increase of dopaminergic VTA neurons
Describe opioid modulation of meso-corticolimbic dopamine system
- Opioids can increase NAC dopamine release via mu-opioid receptors in the VTA
- They reduce GABA receptors, the main inhibitory neurotransmitter, resulting in reduced inhibition
- Opioids with preferential action on kappa-receptors can act presynaptically on dopamine terminals in NAC to reduce dopamine release
How do we measure the rewarding properties of drugs?
- Operational definition of reward = something we and other animals work for
- Drug self-administration procedure: how hard an animal works to get a drug injection e.g. pressing a lever
- Rats self-administer a wide range of opioids intravenously and intracranially, including into VTA (Devine & Wise, 1994)
What is the distinction between reward and pleasure/liking
- Distinction between reward and pleasure/liking = how much a subject works for reward may not directly reflect the ‘liking’ or ‘pleasure’ induced by the reward, but rather ‘wanting’ of or ‘desire’ for the reward
- E.g. people keep wanting the drug but don’t gain pleasure from it
How are opioids related to liking vs wanting
- Facial expressions to sweet or bitter tastes as measures of ‘liking’ (Berridge & Robinson, 2003)
- Nucleus accumbens shell: stimulation of opioid receptors increases ‘liking’, whereas stimulation of dopamine receptors reduces ‘liking’
- Compared to saline solution, varied ‘liking’ expression with sucrose and opioids (opioids increase ‘liking’), whereas dopamine reduces pleasure and even increases aversive reactions to the bitter taste
- Morphine or amphetamine injection into NAC shell
Describe opioid dependence
- Neuropharmacological adaptations to repeated opioid use contribute to dependence:
- Tolerance in response to repeated use leads to reduced acute effects (which may lead the user to increase dose or take a stronger opioid)
- Long-term compensatory changes in neural mechanisms in response to repeated opioid use lead to withdrawal symptoms
- Compensatory changes are opposed to acute opioid effects (chronically, dopamine system may be downregulated and pain system upregulated) – make it hard to stay away from the drug
How may prescription opioids initiate users to heroin abuse and dependence (data from US studies)?
- Since the late 90s/early 2000s, heroin dependent patients in the US have mainly initiated opioid abuse with a prescription opioid (Cicero et al., 2014)
- More recently, with reduction in supply of prescription opioids, heroin again gains in importance as initiating drug (Cicero et al., 2018)
Describe the treatment of opioid dependence
- Detoxification (get rid of highly dangerous opioids), usually assisted by substitution with a long-acting opioid drug – methadone or buprenorphine –, which has lower highs and less pronounced withdrawal symptoms
- Maintenance with methadone or buprenorphine (in clinical setting)
- Reduces mortality from overdose and other causes (Sordo et al., 2017)
- However, substitution drugs have adverse effects, too, and interfere with normal life; the partial agonist buprenorphine may have reduced adverse effects compared to methadone, but high-quality evidence that this significantly improves patients’ life is lacking (Matticket al., 2014)
- Treatment for full abstinence with opioid antagonist (e.g., with naloxone): antagonist will make opioid administration ineffective; typically very low adherence and requires highly motivated patients
