Pain and Analgesia Dr Anne Jackson School of Pharmacy and Biomolecular Sciences University of Brighton

Pain and Analgesia Two themes: Pain, opioid analgesics and endogenous mechanisms Psychological aspects of pain and analgesia

Pain & Analgesia Pain An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. (The International Association for the Study of Pain)

SUBJECTIVE experience Pain & Analgesia Pain The Dimensions of Pain Sensory Dimensions – quality (burning, stabbing etc) & location Affective Dimensions – unpleasantness, distress, anxiety & depression Cognitive Dimension – distraction, suggestion SUBJECTIVE experience

Broad Classification of Pain Type of Pain Duration Characteristics Adaptive? acute seconds eg, contact with hot surface high – prevents or reduces damage subchronic hours to days resolves on recovery – eg, inflamed wound protective chronic or clinical months to years exceeds resolution of damage – often profound psychological components none - maladaptive Pain is not a unitary phenomenon … chronic pain needs to be treated

Basic Pain Pathways spinal cord brain noxious stimulus descending inhibition of pain

proprioception (motion & posture) Pain Perception Sensory information about the world input from periphery as different modalities touch proprioception (motion & posture) temperature nociception (pain) nociception is a distinct modality – not just extreme version of other modalities There are specialised receptors for different modalities.

Periphery - nociceptors hair epidermis dermis free nerve endings Nociceptors are free nerve endings located in the epidermis. They are sensitive to noxious or destructive stimuli. present in most bodily tissues – absent from the brain

Periphery - nociceptors mechanical thermal polymodal – intense mechanical, thermal chemicals released on tissue damage (histamine, PGs) damage induced by chemical release can lead to a sensitized state called hyperalgesia (increase in basal pain sensitivity)

Nociceptors cell bodies located in dorsal root ganglia (or trigeminal ganglia) of the spinal cord axons extend in two directions – to the periphery & to the spinal cord

Afferent neurones from peripheral nociceptors to spinal cord, known as first order neurones or primary afferent fibres Aδ (delta) fibres fast, myelinated, carry information about sharp, well localised pain conduct impulses at the rate of 20 metres per second C fibres slow, unmyelinated, dull aching pain, diffuse localisation conduct impulses at the rate of 1 metre per second When nociceptors are activated, information is transmitted to the spinal cord via primary afferent neurones. This occurs via two main types of neurone – the Adelta fibres and the C-fibres. Fast, myelinated A delta fibers carry sharp, well-localized pain from the surface. When you touch a hot plate, the first percept is a sharp pain that comes almost immediately. This message tells your brain to take emergency measures (withdrawal). Slow, unmyelinated C fibers carry pain from deep within the tissues. The pain is felt as a dull ache which is hard to localize.

neurotransmitter is Substance P primary afferent fibres send information to the dorsal horn of the spinal cord second order neurons cross over & ascend to the brain: spino-thalamic tract neurotransmitter is Substance P primary afferent fibres synapse with second order neurones in the substantia gelatinosa Primary afferent nociceptors enter the spinal cord via the dorsal root and then synapse with second order neurons in the dorsal horn of the spinal cord gray matter. Nociceptive neurons then cross to the contralateral side and ascend predominantly in the spino-thalamic tract.

brain is responsible for perception of pain Brain Sites ascending second order neurones transfer information to the thalamus & cortex brain is responsible for perception of pain

trigemino – thalamic tract information about noxious stimulation from the face follows a slightly different route: trigemino – thalamic tract

Gate Control Theory of Pain Dorsal Horn area where pain can be modulated Gate Control Theory of Pain explains how pain can be reduced by non-painful stimuli eg – bang elbow – non-painful stimulus (rubbing) masks pain

Gate control – Melzak & Wall, 1965 spino-thalamic tract nociceptors

Gate control – Melzak & Wall, 1965 spino-thalamic tract nociceptors mechanoreceptors

Gate control – Melzak & Wall, 1965 nociceptors mechanoreceptors The gate control theory of pain was first proposed by Melzack & Wall in 1965. Within the substantia gelatinosa interneurones can modulate activity of the nociceptors. The interneurones can be modulated by input from mechanoreceptors. This causes the release of a neurotransmitter peptide called enkephalin which inhibits the activity of the nociceptors and therefore reduces pain perception. endogenous opioid neurotransmitter – enkephalin http://www.uth.tmc.edu/nba/neuroscience/s2/chapter08.html

substantia gelatinosa Gate Control of Pain substantia gelatinosa brain peripheral modulation – mechanical stimulus painful stimulus ✗

substantia gelatinosa Gate Control of Pain substantia gelatinosa brain painful stimulus central modulation – emotions, distraction etc ✗

substantia gelatinosa Gate Control of Pain substantia gelatinosa brain painful stimulus best known painkiller – morphine ✗

Opioids Used to Treat Pain OPIUM POPPY papaver somniferum morphine codeine alkaloids, extracted from juices since 4000 BC – ‘plant of joy’

Opioids Used to Treat Pain heroin diacetylmorphine made from morphine that has been extracted from the opium poppy heroin is metabolised to morphine in the body morphine heroin

Morphine - General Properties CNS properties - useful analgesia (an- ‘without’, algesia- ‘pain’) good analgesic – but less effective for neuropathic pain (pain associated with nerves) drowsiness anti – tussive (cough suppressant) euphorigenic – helps with pain (but a reason for abuse)

Morphine - General Properties other CNS properties – not useful pruritis (itching skin; depends on route of administration) skin flushing hypothermia miosis (pupillary constriction) - can be a marker of opioid ingestion miosis mediated by opioid receptors in the oculomotor nucleus of the medulla

Morphine - General Properties other CNS properties – also not useful nausea & emesis mediated by opioid receptors in the area postrema of the medulla can be treated with 5-HT3 – receptor antagonists (eg, ondansetron)

Morphine - General Properties other CNS properties – most serious side effect respiratory depression mediated by opioid receptors in the medulla

Peripheral side effects of morphine GI tract constipation – tolerance does not develop antagonists that do not cross BBB could treat this side effect

Pain killers similar to morphine codeine (methylmorphine) less potent than morphine usually for mild pain & as anti – tussive fentanyl (extremely potent) can be used transdermally useful if oral administration difficult fentanyl

How does morphine produce analgesia? spinal cord brain noxious stimulus descending inhibition of pain inhibiting nociceptive information transfer in the dorsal horn activation of descending inhibition 1 2

Descending Inhibition of Pain important areas in descending control of pain periaqueductal gray (PAG) raphé nucleus neurones originating from these areas can induce stimulation of interneurons (enkephalin) in the dorsal horn

spinal cord inhibition -receptor agonists also act directly at the level of the spinal cord where endogenous peptides act on  - receptors Morphine and other mu-receptor agonists also work at the level of the spinal cord. Mu-receptors located in area where endogenous opioids act. spinal cord inhibition

Complications of Opioid Analgesics morphine, heroin, codeine and fentanyl are  (mu) opioid-receptor agonists both the therapeutic and the side effects of morphine are mediated by  opioid-receptors small ‘therapeutic window’ – therapeutic dose is close to the dose that produces serious side effects (respiratory depression)

Morphine/Heroin Poisoning (Overdose) deaths occur due to respiratory depression clinical overdosage low BP / shock - delayed absorption accidental ‘overdose’ in addicts mixed poisonings in addicts alcohol or benzodiazepines

Morphine/Heroin Poisoning (Overdose) symptom triad coma pinpoint pupils low respiration rate in addicts, needle marks can support diagnosis of poisoning treatment - naloxone (short-acting antagonist acts at mu receptors) small, i.v. doses - repeat until respiratory depression reversed – care not to precipitate withdrawal if patient is a heroin addict

Complications of Opioid Analgesics two further important complications tolerance dependence (later when substance abuse is covered)

Tolerance defined as the need for increasingly higher doses of drug to achieve the desired effect

Tolerance Pharmacologically defined as follows: response The dose-response curve shifts to the right The maximum drug effect does not change acute (single administration) chronic (continuous administration) dose response max

Tolerance dispositional pharmacodynamic dispositional results from changes in the pharmacokinetics of a drug leads to reduced concentrations of drug this usually means a change in rate of metabolism

Tolerance dispositional pharmacodynamic pharmacodynamic ‘behavioural tolerance’ effect reduced but concentrations of drug stay same adaptation has occurred, learning involved

Tolerance tolerance does not develop uniformly to all the effects of a drug opioids tolerance will eventually develop to most of their actions (except anti-diarrheal) mostly pharmacodynamic tolerance (learned, adaptive) and involve classical conditioning

Classical (Pavlovian) Conditioning

Tolerance to Analgesia compensatory responses increase with chronic use & become associated with environmental cues (conditioning) person experiences compensatory response following initial drug effect eventually, environmental cues alone can trigger compensatory responses  tolerance (need to take more drug) analgesia hyperalgesia

Summary classification of pain - acute & chronic 1 basic pathways - dorsal horn; substantia gelatinosa; spino-thalamic tract; thalamus & cortex 2 inhibition of pain; gate control; descending mechanisms 3 basic properties of opioid analgesics, opioid poisoning & respiratory depression 4 how tolerance develops to opioid analgesia through classical conditioning 5

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