Introduction to Pain: An Integrated Approach PDF

Introduction to Pain: an Integrated approach from Neuroscience to Psychology Dr Anna Battaglia Faculty of Life Sciences & Medicine Learning Outcomes (1) Historyof pain Nociceptors and pain pathways Gate control theory of pain Look for the which says what is essential inf...

Introduction to Pain: an Integrated approach from Neuroscience to Psychology Dr Anna Battaglia Faculty of Life Sciences & Medicine Learning Outcomes (1) Historyof pain Nociceptors and pain pathways Gate control theory of pain Look for the which says what is essential information (20 slides) The worst pain a man can suffer: to have insight into much and power over nothing. Herodotus (5th century BC) Pain The word pain is derived from the Latin “poena” and the Greek “poine”, meaning “penalty” or “punishment (from the Greek goddess of revenge). In the book Iliad by Homer (8th-9th BC): distinction between algos - central pain and odyne - peripheral pain (a painful wound) Plato (4th BC) : pain is a sensation and corresponds to the illness itself Hippocrates (4th BC): pain happens to a body, suffering happens to a person ◦ He was the first to advice women giving birth to chew willow leaves (containing salicylic acid) Aristotle (3rd BC): heart the seat of feelings and pain was a feeling Aristotelian concept predominated for 2,000 years   Galen (AD 129-199) was the first physician thinking that pain was a sensation in which the brain and nerves played an important role.  “Nature has had a triple motive in arranging the nerves: it provided for sensibility in the perception organs, movement in the locomotion organs and the faculty to recognize any lesions sustained in all the others”. “Pain is useless to the pained’ Pain in the Middle Ages had powerful spiritual and religious contexts, but it was also an important academic issue for physicians. In most cases celebration or resigned acceptance of pain seem to be common attitudes of the period in Western Europe (F. Salmon)  In the East it was the Islamic golden age. A famous Persian philosopher was Ibn Sina or Avicenna(980-1038 AD). “He suggested that the true cause of pain was a change of the physical condition of the organ whether there was an injury present or not.”  Avicenna wrote extensively about brain anatomy and its role as a centre for pain sensation. Both Galen and Avicenna believed that the brain was the principal organ for perception of pain.” (Tashani, 2010).  The Renaissance: Leonardo da Vinci (1452- 1519 AD).  Due to his amazing skills of dissecting and drawing he realized the fine relationship between the spinal cord, peripheral nerves and roots and connections to the brain.  “For Leonardo pain was a sensation mediated by nerves that also carry information about touch” (Perl)  Rene Descarte s The1596-1640 intensity of pain is directly related to the amount of associated tissue injury (specificity theory). Nerves are tubes inside which fine threads transmit sensory stimuli to the brain.  “The late nineteenth century saw a dramatic shift in conception and pain considered from a ‘gift from God’ to a physiological conundrum and medical challenge” (L. Bending).  Intensity theory (pain not a unique modality but emotional state produced by stronger than normal stimuli) vs specificity theory  CS Sherrington (1857-1952) in 1906 discovered specialized nerve cell called nociceptors whose molecular sensors are activated by harmful chemical or physical conditions.  What is Pain? Painis a multidimensional sensory and emotional subjective experience. Targets of Pain Management Programm From: http://accesspsychology.ie/ coping-with-pain-pain-management Today’s pain definition: An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. International Association for the Study of Pain (IASP) Recently re defined with minor tweaks overall SENSING DAMAGE: THE NOCICEPTORS SENSING DAMAGE:THE NOCICEPTORS  Noxious stimuli detected by damage-sensing neurons, nociceptors whose specialized free nerve endings are in skin, muscle and viscera and cell bodies in the dorsal root ganglia (DRG);  They respond to multiple types of stimuli (high mechanical pressure, high/low temperatures, chemicals) which will only generate electrical activity if they are over a certain threshold.  Receptors at sensory terminals convert such stimuli into electrical activity (e.g. TRPV1): the larger the change in voltage at the terminal, due to influx of Na+ and Ca2+ trough receptors forming ion channels, the greater the number of action potentials generated. SENSING DAMAGE:THE NOCICEPTO A bit of anatomy http://www.wellcome.ac.uk/en/pain/microsite/science1.ht ml General organization of pain pathways Ascending pathways Spinothalamic: Discriminative aspect of nociception. Fast pain Spinoreticular: Responsible for arousal and affective (unpleasantness) aspects. Dull pain  Pain processing in spinal cord Termination points of sensory neurons in the spinal cord. Most neurons involved in pain signals terminate in laminae I and II at the top, or dorsal end of spinal cord contacting cells transmitting information in regions of brain involved with the responses to pain and its perception.  Pain processing in the brain  Pain matrix (areas in the brain potentially responsible for processing nociceptive inputs and generating the pain experience) ….but  Pain matrix concept has been revisited (see papers from G Iannetti, UCL) OPIOIDS The component of opium responsible for analgesia is morphine. Pert and Snyder (1973) demonstrated specific opiate receptors in brain tissue. Opiate receptors: µ, , . Hughes and Kosterlitz (1975) identified the first endogenous opioids, small peptide molecules called Met-enkephalin and Leu-enkephalin. Since then, several other endogenous opiates have been discovered. These include the endorphins and dynorphins. 22  PAG:periaqueductal gray, rich in opioid receptors and enkephalins(electrical stimulation of PAG produces analgesia); PAG neurons’ axons end on serotoninergic neurons in the medulla  RVM rostro ventromedial medulla: important area both for inhibition and facilitation of nociceptive processing; bidirectional central control of nociception Weaknesses of tying pain only to the stimulus (specificity theory)  Does not account for the presence of pain in certain situations e.g., for pain without damage (e.g., phantom limb pain), or damage without pain (Beecher - WWII soldiers) or forms of chronic pain  Moreover, the role of psychological factors is not taken into account, so…… The Gate Control Theory of Pain (1965) Melzack and Wall suggested that small interneurons in the dorsal horn act as a gate which controls the amount of excitation of the transmission‘gate’ cells. closed (low pain) T small diameter afferent fibre ‘gate’ open ascending pathways to the brain (high pain) T Never again, after 1965 could anyone try to explain pain exclusively in terms of peripheral factors Gate control theory of Pain Which Factors Regulate the Gate? 1. Amount of activity in pain fibres 2. Amount of activity in other peripheral fibres (activation of mechanoreceptors Aß fibres) 3. Messages descending from brain, e.g. emotions (anxiety, relaxation), mental conditions (boredom, learning) Thus: psychological factors influence pain perception by regulating the gate mechanism. Learning Outcomes (2) Pain components Placebo effect in analgesia Pain is a subjective experience and has three components sensory-discriminative sense of intensity location and duration affective-motivational unpleasantness and desire to escape it cognitive component involving judgments, beliefs, memories, perception of environment and patient's own Multidisciplinary approach to pain  In parallel with changes in the conceptualization of pain, changes in its treatment have occurred: ◦ e.g., Multidisciplinary approach. Treatment of pain involves combination of medical treatment including drugs and surgery, physical therapy, and psychological approaches such as Cognitive Behavioral Group therapy etc. ◦ Cutting nerves and pathways has been replaced by methods for modulating inputs e.g., relaxation, hypnosis, acupuncture and pain-management aids such as TENS, heat packs etc. ◦ Placebo as a treatment?? From: http://www.overcomingpain.com/history.html  Placebo effect: a modern definition  Itis a psycho-socio- biological phenomenon activated when the patients believes in an effective therapy and so expects a reduction of symptoms.  The placebo effect is the outcome following a “dummy” treatment or the administration of an inert medical treatment, which can be pharmacological or not. 31  Placebo as topic of research  Placebo effect, has been for long considered a problematic issue to deal with in clinical trials (placebo groups in double-blind trials were introduced in early 1900s)  Now has become itself a target of scientific inquiry. The psychosocial context tells the patient’s brain to expect a therapeutic effect. As a result, neurobiological events occur in the brain via unconscious and / or conscious mechanisms, bringing about the release of effector molecules. These cause physiological changes in the brain and other organs that can generate a 32 therapeutic effect.  Placebo-related effects  No placebo is given and effects are attributed to the influence of context surrounding the treatment on the patient’s brain.  Verbal suggestions of improvement or worsening can be given alone, thus inducing expectations about the outcome. from Benedetti (2008) 33 Possible mechanisms involved Different mechanisms by which the psychosocial context Cascade of biochemical events acts in the brain following placebo on the patient’s brain. administration. 34  Open-hidden paradigm Telling a patient that a painkiller is injected but only saline is, is as potent as 6-8 mg of morphine 35 Open vs. hidden treatment 36 Nature Review Neuroscience by T Wager (2015) 37 http://www.nature.com/nature/journal/v535/n7611_supp/full/ How can we use placebos in medicine effectively?  Colloca suggests that, by taking advantage of learning mechanisms, doctors could give placebos honestly and reduce the amount of medication. For example, a doctor might prescribe a blister pack of painkillers, and tell the patient that it contains both drugs and placebos — but not which pills are which. Earlier this year, Colloca and her colleagues reviewed 22 studies that used similar techniques, covering conditions such as insomnia, autoimmune diseases and pain. They concluded that these approaches have the potential to reduce side effects (although some of these may be conditioned responses, too), limit problems with drug dependency and toxicity, and reduce costs.  Benedetti loves the idea. “This is one of best applications of placebos in clinical practice,” he says. In a trial published in February, he showed that in people with Parkinson's disease, pre- conditioning with the drug apomorphine made patients respond to a placebo just as strongly as they did to the active drug. Alternating drugs and placebos might delay the development of tolerance, he suggests.  Kaptchuk is going one step further. For conditions such as chronic pain, for which placebo effects are large, drugs aren't very effective and taking them can have downsides, he suggests sometimes ditching medication altogether and openly giving placebos. He made headlines in 2010 with a placebo study for irritable bowel syndrome (IBS) in which patients were told that they were receiving a sugar pill. “Historically, the assumption has been that deception or concealment is necessary for placebos to work,” Kaptchuk says. “My logic was that maybe we could tell patients upfront that placebos may work and tell them to give it a try.” The results were startling: 59% of patients who knowingly took sugar pills reported adequate relief from their symptoms, compared with 35% in the no- treatment group — better than most IBS drugs, he adds. “I was very surprised by the results,” says Kaptchuk, “even though I hoped it would work.” Learning Outcomes (3) Differenttypes of pain Pain hypersensitivity Acute vs Chronic Pain Pain Psychology Is there more than one type of pain?  Yes, we can usefully divide pain in: Pain adaptive maladaptive Neuropathi Nociceptive Inflammatory Dysfunctional c Pathological pain  Acute inflammatory response via neutrophi https://www.nidcr.nih.gov/news-events/nidcr-news/2022/inflammation- l activation protects against the developm may-curb-not-cause-chronic-pain ent of chronic pain. Parisien M, Lima LV, Dagostino C, El- Hachem N, Drury GL, Grant AV, Huising J, Verma V, Meloto CB, Silva JR, Dutra GGS, Markova T, Dang H, Tessier PA, Slade GD, Nackley AG, Ghasemlou N, Mogil JS, Allegri M, Diatchenko L. Sci Transl Med. 2022 May 11;14(644):eabj9954. doi: 10.1126/scitranslmed.abj9954. Epub 2022 May 11. PMID: 35544595. 44  Pain hypersensitivity  Painsystems need to be sensitive enough to detect potentially harmful stimuli.  Ifthey become too sensitive will cause us pain that provides no benefit.  Thishypersensitivity arises because our pain pathways actually increase in sensitivity when they relay pain messages.  Pain hypersensitivity takes two forms: ◦ Thresholds are lowered so that stimuli that would normally not produce pain now begin to, so called allodynia ◦ Responsiveness is increased, so that noxious stimuli produce an exaggerated and prolonged pain or hyperalgesia.  What are the mechanisms involved in pain hypersensitivity? Peripheral Central sensitizati sensitizati on on Reduction in threshold and Is an increase in the excitability of increase neurons within the central nervous in responsiveness of peripheral system, triggered by a burst of ends of nociceptors. activity in nociceptors, which alters the strength of synaptic Sensitization arises due to the connections action of inflammatory (activity-dependent synaptic chemicals (ATP, PGE2, NGF). plasticity) between nociceptors and spinal cord neurons.  Acute vs. Chronic pain  AcutePain: acute pain  ChronicPain: Pain that or nociceptive pain lasts past normal healing occurs when a strong time (typically > 3 to 6 noxious stimulus months). impacts the skin or ◦ Spine deep tissue, and ◦ Hips, shoulders, knees activates the ◦ Ischaemic leg ulcers nociceptive pathways ◦ Chest pain ◦ sickle cell crisis, post- ◦ Chronic Visceral pain operative, trauma, tooth- ◦ Headache ache ◦ Peripheral neuropathy ◦ Chronic post-surgical pain Contributing factors to chronic pain development Badly managed acute pain Previous bad pain experiences Pain goes on for longer leading to permanently sensitized dorsal horn Surgical complications Activation of descending pathways which facilitate pain transmission Long-term alterations of the epigenome Emotionally sensitive patient Difficulty understanding Poor coping skills Brain wiring (e.g. corticolimbic system) Social determinants of chronic pain Socio-economic background Population studies reliably ◦ Low level of education show that the prevalence ◦ Perceived income inequalities of chronic pain is inversely ◦ High level of neighbourhood related to socio-economic deprivation factors Employment status and Those who are socio- occupational factors economically deprived are ◦ People not in employment not only more likely to due to ill health or experience chronic pain disability(bidirectional than people from more relationship) affluent areas, but they ◦ Occupational risk factors (e.g., poor job control, are also more likely to expectations to return to experience more severe work, lack of work autonomy, pain and a greater level of job satisfaction, manual work pain-related disability https://www.ncbi.nlm.nih.gov/pmc/articles/ An example of how a state of mind can influence the pain response  Catastrophizing in pain  “Only a modest relationship exists between identifiable physical pathology and a patient’s report of pain symptoms”.  “Catastrophizing is a set of negative emotional/cognitive processes that involve rumination and pessimism, perception of helplessness, and magnification of pain- related symptoms” (Campbell & Edwards, 2009) Psychology of Pain Relieffrom pain is not the most required action, but the following are: – Perceiving evaluation as complete. – Feeling the received explanation for treatment. – Believing that treatment improved daily activity. IMMPACT (Survey of people in Pain) Pain sufferers rated 8 (0-10) the following areas they would like to see improved in their life: – Enjoyment of life in general – Fatigue – Emotional Well-being – Weakness – Staying asleep at night  Satisfaction of medical treatments for chronic pain overall poor  Cognitive Behavioural Methods  Pain programs which include psychological treatments increase improvement  Concept that suffering is normal in human life  In some cases of chronic pain control is more part of the problem than a solution  Psychological inflexibility  ACT (Acceptance and Commitment Therapy)  Successful treatment of pain depends on Behavior change https://onlinelibrary.wiley.com/doi/abs/ The lady who feels no pain, is never anxious, is happy, heals quickly and…has memory lapses..all this caused by TWO mutations. https:// https:// www.bbc.co.uk/ bjanaesthesia.or news/uk- g/article/S0007- scotland- 0912(19)30138- highlands- 2/fulltext islands- 47719718 FAAH: fatty-acid amide hydrolase; anandamide (AEA), a fatty acid amide, that act as endogenous ligands for cannabinoid We all must die. But if I can save him from days of torture, that is what I feel is my great and ever new privilege. Pain is a more terrible lord of mankind than even death himself. Albert Schweitzer (1875-1965) 1952 Nobel Peace Prize Laureate AVAILABLE IN THE LIBRARY  Physiology of pain (Oct 2019) You can find this very useful up to date resource on the Physiology of Pain here: https://www.sciencedirect.com/journal/ current-opinion-in-physiology/vol/11/ suppl/C/vol/11/suppl/C/vol/11/suppl/C 60 For recent news on Pain research go to: http://www.painresearchforum.org/news 2017 https://www.painresearchforum.org/news/82919-highlights-2017- annual-meeting-american-pain-society-part-1  An interesting the link between diet, inflammation and chronic pain: “Nutrition, inflammation, and pain: how diet cranks pain up—and dials it down” 31 Aug 2020 https://www.painresearchforum.org/forums/webinar/148341-prf-semi nar-%E2%80%93-neuroimmune-glia-interactions-neuropathic-pain-ho w-does 8 Sept 2020 https://www.painresearchforum.org/forums/webinar/149206-prf-semi nar-%E2%80%93-pain-and-brain-impact-and-influence-descending-m odulatory 2022 Pain News 2023 Pain research Forum moved to the International Association for the Study of Pain (IASP) website Cox, J et al., (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature, 444: 894-898 Kim et al., (2012) The role of Drosophila Piezo in mechanical nociception. Nature, 483(7388):209-12 Legrain V.et al., (2011) The pain matrix reloaded. A salience detection system for the body. Progress Neurobiol,93 (1):111-24 Marchant J (2016) Placebos: Honest Fakery. Nature 535. S14-S15 Mogil, JS (2009) Animal models: progress and challenges. Nature Reviews Neuroscience 10, 283-294 Perl, E (2011) Pain mechanisms: A commentary on concepts and issues. Progress Neurobiol, 94:20-38 Perl, E (2007) Ideas about pain, a historical view. Nature Rev Neuroscience, 8: 71-80 Todd AJ (2010) neuronal circuitry for pain processing in the dorsal horn. Nature Reviews Neuroscience 11: 823-836 Turner, J and Aaron, L. A. (2001) Pain-Related Catastrophizing: What Is It? Clinical Journal of Pain, 17(1):65-71 Wall, P and Melzack, R. Textbook Pain 5th Ed. (2005) Chapters 1 and 5. Wood, JN et al., http://www.wellcome.ac.uk/en/pain/microsite/science1.html Woolf CJ (2004) Pain: moving from symptom control toward mechanism-specific pharmacologic management.  Beggs S, T Trang & MW Salter (2012) P2X4R+ microglia drive neuropathic pain. Nature Neuroscience, 15 (8): 1068-1073  Craig KD and J Versloot (2022) Psychosocial perspectives on chronic pain in Clinical Pain Management: a practical guide (2nd ed), Chapter 4, Wiley Blackwell  Foell J (2015) The social determinants of pain: from bodywork to social work. Oxford textbook of musculoskeletal medicine, Chapter 5, Oxford Academic press  Foster E (2015) Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch. Neuron Mar 18;85(6):1289-304.  Denk F, McMahon S & I Tracey (2014) Pain vulnerability: a neurobiological perspective. Nature Neuroscience, 17 (2): 192-200  Mills S EE, Nicolson KP and BH Smith (2019) Chronic pain: a review of its epidemiology and associated factors in population-based studies. British Journal of Anaesthesia, 123 (2): e273-3283  Navratilova E and Porreca F (2014) Reward and motivation in pain and pain relief. Nature Neuroscience, 17 (10): 1304-1312  Waxman SG & GW Zamponi (2014) Regulating excitability of peripheral afferents: emerging ion channel targets. Nature Neuroscience, 17 (2):153-163