LO 18 Review Pain pathways and pharmacology of pain management in osteoarthritis (Halima)

Pain is not a sense, like touch, sight, or hearing. Pain is an emotion

Pain pathways Both A (localised shooting, stabbing pain) and C (chemical, thermal, mech - dull diffuse), fibres enter the spinal cord at the dorsal horn. The dorsal roots are made of layers, known as laminae, into which the sensory nerve fi bres enter. Synapses are made with the transmission neurons that direct the impulse across the spinal cord to motor neurons and can elicit a refl ex arc from the offending source of the noxious stimuli. Alternatively, the impulse may ascend the spinal cord to the brain. Second-order neurons send their sensory inputs to the thalamus via two ascending pathways: the dorsal column medial-lemniscal system and the anterolateral system (includes the spinothalamic, spinoreticular, and spinotectal fibers). The axons of 2nd order neurons synapse on 3rd order neurons in the thalamus. The Thalamus is the crucial relay for the reception and processing of nociceptive information in route to the cortex. Axons terminating in the lateral thalamus mediate discrimative aspects of pain. Axons terminating in the medial thalamus mediate the motivational-affective aspects of pain (emotional aspects of pain; attention to and memory of pain). These 3rd order neurons in the thalamus in turn send their axons to the cerebral cortex. Note: neurons in the lateral thalamus (for discrimination) project to the somatosensory cortex. Neurons in the medial thalamus (for affective aspects of pain project to other areas of cortex (prefrontal, insular and cingulate gyrus). As important as the ascending pathways, are descending pathways that modulate the incoming signal. These are predominantly noradrenergic and serotonergic, and can be modulated by stimulation of opiate receptors. Descending tracts leave the reticular formation within the brain, travel along the spinal cord and synapse with the transmission and interneurons within the substantia gelatinosa. The descending tracts function in order to modulate incoming messages from peripheral nerves. Thus, they act as a filter and partial inhibitor of the messages ascending the spinal cord from the nociceptors. This limits transmission of the impulses from the sensory A and C fibres along the transmission fibres. The descending nerve fibres arise at the periaqueductal grey within the reticular formation and flow into the medulla. From the nucleus raphe magnus in the medulla, impulses then pass down the dorsolateral tracts in the spinal cord to connect with the transmission neurons and interneurons in the substantia gelatinosa of the spinal cord. The major

ne ns e e escending tracts is serotonin which stimulates interneurons within the substantia gelatinosa to release peptides noradrenaline and endogenous opioids such as endorphins enkephalins and dynorphines All of the areas associated with pain processing are rich in opiate receptors which could e pla the in actions of our analgesic preparations

Almost 1 in 5 patients seen in general practice has some form of chronic pain, with symptomatic osteoarthritis and back complaints the most common conditions Chronic OA pain would be classified s deep so ti or mus uloskelet l p in and chronic pain is defined as y being that which lasts for longer than 3 months (as per lecture notes - though some te ts say 6 months? , y associated with functional, psychological and social problems that can negatively impact a person s life and y often reported as Torture and Suffering. The treatment however should not be delayed for that length of time and should be multidimensional for OA patients as shown in the diagram at left. The main goals of pharmacological interventions for OA are relievin p in and redu in inflammation. Treatment aims to improve functioning and quality of life while minimising the risk of side effects ain Mechanisms in OA (quick review of sensitisation and h peral esia this hopefull helps understandin of pharmacol choices Inflammation in the joint causes peripheral sensitisation (increase of sensitivity of nociceptive primary afferent neurons and central sensitisation (hypere citability of nociceptive neurons in the central nervous system). The processes of sensitisation are thou ht to be the basis of arthritic pain that appears as spontaneous pain (joints at rest) and h peral esia (augmented pain response on noxious stimulation and pain on normally nonpainful stimulation). Sensitisation also facilitates efferent neuronal processes through which the nervous system influences the inflammatory process. Peripheral sensitisation is produced by the action of inflammatory mediators such as bradykinin, prostaglandins, neuropeptides, and cytokines which activate corresponding receptors in proportions of nerve fibers. In addition, the expression of receptors, for example, bradykinin and neurokinin 1 receptors, is

  

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upregulated during inflammation. The development of hyperexcitability of spinal cord neurons is produced by various transmitter/receptor systems that constitute and modulate synaptic activation of the neurons. The key transmitter is glutamate that activates N-methyl-d-aspartate (NMDA) and non-NMDA receptors on spinal cord neurons. Blockade of these receptors prevents and reduces central sensitisation. Excitatory neuropeptides (substance P and calcitonin gene-related peptide) further increase central sensitisation. Central sensitisation also is facilitated by mediators that have complex actions (e.g., prostaglandin E(2)). Spinal PGE(2) binds to receptors at presynaptic endings of primary afferent neurons (thus influencing synaptic release) and to receptors on postsynaptic spinal cord neurons. The administration of PGE(2) to the spinal cord surface produces changes of responsiveness of spinal neurons similar to peripheral inflammation, and spinal indomethacin to the spinal cord attenuates development of hyperexcitability significantly. Pain management in osteoarthritis
Sites of action of analgesics y Peripheral nociceptors NSAIDs, Local anaesthetics, Opioids y Spinal cord Opioids, Local anaesthetics, NSAIDs y Brain stem and above Opioids, ?NSAIDs, Paracetamol

NSAIDS inhibit COX pathways and thus inhibit prostaglandins There are two types of cyclooxygenase enzyme, namely COX-1 and COX-2. COX1 is a constitutive enzyme expressed in most tissues, including blood platelets. It has a house-keeping role in the body being involved in tissue homeostasis. COX-2 is induced in inflammatory cells when they are activated, and the primary inflammatory cytokines-interleukin-1 (IL-1) and tumour necrosis factor(TNF- ) are important in this regard. Thus COX-2 is responsible for the production of the prostanoid mediators of inflammation. Mosttraditional NSAIDs in current use are inhibitors of both isoenzymes, though they vary in the degree of inhibition of each. It has become clear that the anti inflammatory action of the NSAIDs is mainly related to their inhibition of COX 2 and that, when used as anti-inflammatory agents, their unwanted effects -particularly those affecting the gastrointestinal tract-are largely a result of their inhibition of COX -1. Effects o NSAIDs have three major pharmacologically desirable actions, all of which result mainly from the inhibition of arachidonic acid cyclooxygenase in inflammatory cells (the COX isoenzyme), and the resultant -2 decrease in prostanoid synthesis. They are: i. An anti-inflammatory action: the decrease in vasodilator prostaglandins (PGE2, prostacyclin) means less vasodilatation and, indirectly, less oedema. Accumulation of inflammatory cells is not reduced. An analgesic effect: decreased prostaglandin generation mean less sensitisation of nociceptive s nerve endings to inflammatory mediators such as bradykinin and 5 -hydroxytryptamine. Relief of headache is probably a result of decreased prostaglandin -mediated vasodilatation.

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An antip r tic e ect: this is part owi to a decrease i the mediator prostaglandin (which is generated in response to the inflammator pyrogen interleu in-1) that is responsi le for elevating the hypothalamic set-point for temperature control, thus causing fever

Ad er e ects: Unwanted effects, owing largely to inhi ition of cyclooxygenase-1, are common, particularly in the elderly, and include:
y y y y y y

Dyspepsia, nausea and vomiting; also gastric damage in chronic users, with ris of haemorrhage, resulting from abrogation of the protective effect of prostaglandin (P ) on gastric mucosa. Skin reactions. Reversible renal insufficiency (in individuals who have noradrenergic - or angiotensin-mediated vasoconstriction) through lack of compensatory P E -mediated vasodilatation. 'Analgesic-associated nephropathy'; this can occur following long-continued high doses of NSAIDs (e.g. paracetamol) and is often irreversible. Less commonly, liver disorders, bone marrow depression. Bronchospasm in 'aspirin-sensitive' asthmatics.

AVO D in people with heart failure, risks of HF ,hypertension, renal failure, diabetes and aspirin -induced asthma and GI risks Combining an NSAID with paracetamol allows lower NSAID doses to be used. Intermittent use (for example, before activity or during a flare in pain) has a lower risk of adverse effects than continuous use. Paracetamol: mode of action not fully determined but similar to NSAIDs. Analgesic affect due to the inhibition of prostaglandin synthesis. Antipyretic effect due to the reduced producti on of prostaglandins in the hypothalamus. Opioids Nocisensors can be inhibited by opioids (desensitisation) and stimulated by prostaglandin E or bradykinin, which is released in response to inflammation (sensitisation). Endogenous opioids (e.g. dynorphin, enkephalin, endorphin) and exogenous opioids (e.g., morphine) as well as inhibitors of prostaglandin synthesis are therefore able to alleviate pain (analgesic action). A weak opioid may be considered an alternative to an NSAID when paracetamol alone is inadequate, particularly for people at high risk of NSAID-induced adverse effects. Guidelines also suggest that a weak opioid be added if a patient s pain does not respond adequately to an NSAID (with or without paracetamol). Codeine is the weak opioid o choice. Strong opioids can be used when other analgesics do not provide sufficient pain relief or are unsuitable because of adverse effects. Morphine is usually considered the strong opioid of first choice because of familiarity, cost and the range of formulations available. Oxycodone and hydromorphone are alternatives for people who cannot tolerate morphine. Regular rather than as-needed doses should be prescribed for around-the-clock pain control (if needed).
Relevance to the case Diclofenac is an NSAID that inhibits cyclooxygenase thereby reducing prostaglandin synthesis. It tends to concentrate in synovial fluid. Paracetamol is an analgesic. These were initially prescribed by the GP who got the boot He simply prescribed Diclofenac (NSAID) 50mg twice daily and Paracetamol (non-opioid analgesic)1g twice daily and told her she would get better in a few weeks. This has made little difference to her pain and stiffness . She has RA thus needs the DMARD therapy.
Refs Lecture notes L@G; Porth - Chapter 39; National Prescribing Service Limited. NPS News 47: Analgesic options for pain relief. 01/08/2006. Royal Australian College of General Practitioners. Guideline for the Non-Surgical Management of Hip and Knee Osteoarthritis. July 2009.

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