AUTHOR: Donna Cosgrove PhD MPSI
Donna graduated with a BSc in Pharmacy from the Royal College of Surgeons in Ireland. She then returned to university to complete a MSc in Neuropharmacology. This led to a PhD investigating the genetics of schizophrenia, followed by a postdoctoral research position in the same area. Currently Donna works as a pharmacist in Galway, and as a clinical writer.
60 Second Summary
The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.
The reason we experience pain is to notify the body of a stimulus in order to avoid further tissue damage. It is usually proportional to the severity of the injury, and resolves when the tissue heals fully.
In pain perception, three main stages generally occur, firstly pain sensitivity, then pain transmission from the periphery to the DH, and finally, transmission of these signals to the higher brain, e.g cortex, through nerves in the central nervous system (CNS).
Pain is strongly associated with self-care management and acute pain is responsible for consumption of large quantities of over the counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDS). Pharmacist-led management of pain, including the identification of the cause and knowledge of the treatments available, helps optimise outcomes in selfmedicating people.
Ibuprofen is the first line treatment recommendation for a range of aches and pains including lower back pain, period pain and toothaches. Although aspirin can also be used for many aches and pains, other NSAIDs like ibuprofen tend to be better tolerated, so are the preferred option.
There are no specific clinical guidelines that provide information on how to manage acute pain with OTC analgesics, but there are a few available that are still relevant such as the NICE management of acute postoperative pain, and several indication specific guidelines for e.g headache, back pain, dysmenorrhoea, and sprains and strains.
Management of Acute Pain in Pharmacy
Introduction
Pain is a distressing sensation, as well as an emotional experience. 1 The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. IASP expand further with these points to put the definition in context: 2
• Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors.
• Pain and nociception are different phenomena: pain cannot be inferred solely from activity in sensory neurons.
• Through their life experiences, individuals learn the concept of pain.
• A person’s report of an experience of pain should be respected.
• Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being.
• Verbal description is only one of several behaviours to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain.
The reason we experience pain is to notify the body of a stimulus in order to avoid further tissue damage. It is usually proportional to the severity of the injury, and resolves when the tissue heals fully. Acute pain lasts for less than 3 months and is most commonly caused by musculoskeletal conditions. Chronic pain persists beyond the tissue healing time, or beyond three months. 3 Prolonged pain which lasts for longer than the expected period of healing can be caused by an inappropriate increase of afferent input into the dorsal horn (DH), leading to central sensitisation. 1
Types and Causes of Pain
The experience of pain occurs through the activation of receptors in the primary afferent fibres: the unmyelinated C-fibre and myelinated Aδ fibre. These receptors are only activated in the presence of noxious stimulus and are normally quiet. Three types of neurons that exist in our body are sensory neurons (afferent neurons), interneurons (which relay the signals between afferent and efferent neurons) and motor neurons (efferent neurons). (See figure 1 on page 42)
In pain perception, three main stages generally occur, firstly pain sensitivity, then pain transmission from the periphery to the DH, and finally, transmission of these signals to the higher brain, e.g cortex, through nerves in the central nervous system (CNS). This pathway carrying the signal to the brain is the ascending pathway, and the nerves that connect the brain to e.g. muscles involved in reflex are the descending pathway. 1
• Transduction occurs initially. The painful stimulus is converted to chemical tissue events, then chemical tissue and synaptic cleft events are converted into electrical events in the neurons, and finally electrical events in neurons are transduced as chemical events in the synapses.
• Transmission then occurs, i.e. the propagation of electrical events along the neuronal pathways and across synapses.
• Modulation then takes place at all levels of nociceptive pathways through the primary afferent neuron, DH and higher brain centres, up or downregulating the sensation.
There are multiple types of nerve fibres in the body that have different roles. Based on the velocity of a conducted impulse, axon’s diameter, and function of an axon, the sensory (afferent) neurons are classified into three main groups—Group A, B and C.
• Aα nerve fibres are the thermal and mechanical nociceptors. They are also the smallest myelinated nerves, with a relatively fast conduction velocity.
• Aδ fibres are responsive towards short-lasting and pricking pain.
• Group B nerve fibres are mainly nociceptive in function with moderate conduction velocities, and include those of the autonomic nervous system (ANS) and general visceral afferent fibres.
• Group C nerve fibres are unmyelinated and have a relatively slow conduction velocity. They are polymodal, activated by thermal, mechanical and chemical stimuli. The activation of C-fibres gives rise to poorly localised sensations, such as burning sensation of the skin.
Motor (efferent) neurons carry the impulses of motor signals out from the spine to the peripheral effector organs, the skeletal muscle and smooth muscles. Once the nociceptive signal from the ascending pathway reaches the somatosensory cortex, the descending pain modulation pathway is triggered. Descending pain control pathways can be facilitatory as well as inhibitory: facilitatory pathways enhance pain perception whereas inhibitory pathways suppress pain perception. 4
Pain can be grouped into three different classifications: nociceptive, neuropathic, and inflammatory:
• Nociceptive: Aδ and C-fibres are mostly found in superficial organs, such as the skin, whereas deeper structures such as muscles and joints are mainly supplied with C-fibres. There is an additional nociceptor type called silent nociceptors.
These are located in the viscera and are usually insensitive to mechanical stimuli, but can be sensitised by the chemical mediators produced during inflammatory reactions.
• Neuropathic: this type of pain generally serves no purpose. It is commonly described as nerve injury or impairment and is associated with allodynia (central pain sensitisation). Nerve neurochemistry can be damaged after compression, stretching, or hyperexcitability propagated from other peripheral nerves.
• Inflammatory: This is a normal biological response to harmful stimuli that is required to start tissue repair. Neutrophils are usually the first cells to gather at the site of injury. Redness and swelling at the site of injury is due to the increased blood flow and increased vascular permeability, which can also induce pain. Chemical inflammatory mediators including 5-HT, kinins, histamine, nerve growth factors (NGF), adenosine triphosphate (ATP), prostaglandins (PGs), glutamate, leukotrienes and nitric oxide (NO) are produced from the necrotic tissues during inflammation, and interact to activate nociceptors within the inflamed area.
Hyperalgesia is the natural occurrence of enhanced pain perception at the site of injury due to the lowered pain threshold to thermal/mechanical pain stimuli. PGs are the main culprits for receptor sensitisation. Some inflammatory mediators activate receptors outside the trauma site, covering a larger area than is actually injured.
Allodynia describes central sensitisation that leads to a pain response from a stimulus that normally does not provoke pain, such as a light touch. Both hyperalgesia and allodynia occur due to the increase of prostaglandin E2 (PGE2) in the inflamed tissue after activation of the COX pathway in the DH of the spinal cord.
There are a range of endogenous compounds responsible for the generation of pain: 1
• Tachykinins (substance P, neurokinins A and B) are neuropeptides produced in the periphery that bind to neurokinin type receptors, NK1, 2 and 3, to elicit excitation.
• Calcitonin Gene-Related Peptide (CGRP) is a peptide in both the CNS and PNS. CGRP receptors (calcitonin receptor-like receptors) are found in the nucleus accumbens, meaning that CRGP mediated pain transmission is controlled centrally.
• Bradykinin, produced locally at the site of inflamed tissue, binds to the bradykinin receptors (B1 or B2). It initiates production of other inflammatory mediators, as well as being responsible for nociceptor sensitisation to heat stimuli.
• Cytokines are released following degradation of e.g. mast cells during inflammation. Platelet activating factor (PAF) causes 5-HT production, which leads to plasma extravasation and pain. Histamine is also produced after mast cell granulation, adding to inflammation. Cytokines like interleukin 1β (IL-1β) and tumour necrosis factor α (TNFα), strong proinflammatory molecules that promote hyperalgesia, are also present.
• Prostaglandins are produced from the action of cyclooxygenase (COX) on arachidonic acid (AA). PGE2 (from COX 2, binds to prostaglandin E2 receptors 1-4) and PGI2 (from COX1, binds to prostaglandin receptor IP) are two major PGs that lead to afferent sensitisation.
• Leukotriene B4 is produced within the leukocytes, and is responsible for recruiting neutrophils to the site of tissue damage, as well as promoting cytokine production.
• Adenosine triphosphate (ATP) is an intracellular messenger released locally by damaged tissues and directly stimulates its receptors.
• Nerve Growth Factor is a neuropeptide released at the site of injury causing rapid onset of hyperalgesia after activation of the NGF receptor, widely expressed in primary afferent neurons. It also causes further mast cell degranulation.
• Glutamate is the most common excitatory neurotransmitter, and is released by the sensory afferents to modulate nociception.
The following mediators act to mitigate the sensation of pain:
• GABA is the most widely distributed inhibitory neurotransmitter. It can inhibit the sensation of pain.
• Opioid peptides (enkephalin and dynorphin) bind to mu, delta and kappa opioid receptors, widely distributed throughout the body. These inhibit the release of excitatory neurotransmitters, reducing pain sensation.
• Cannabinoids (most notably tetrahydrocannabinol, THC) bind to CB1 (brain and spinal cord) and CB2 receptors (predominantly in the immune system). They result in a reduction of neuronal excitation and mast cell degranulation.
Pharmacy Role in Acute Pain Management
Pain is strongly associated with self-care management and acute pain is responsible for consumption of large quantities of over the counter (OTC) non-steroidal antiinflammatory drugs (NSAIDS).
Pharmacist-led management of pain, including the identification of the cause and knowledge of the treatments available, helps optimise outcomes in selfmedicating people. 5 It is important to initiate conversations with patients about what they have taken before and how in order to help improve efficacy and safety. The underlying cause of pain should be treated where possible, and the full therapeutic dose tried before switching to an alternative analgesic. For this reason, combination analgesics should not be used as the first line in some cases to allow independent titration of single constituent medicines and assessment of efficacy.
The aims of pain management should be discussed with each individual, but may include some or all of the following: 3
• Reducing the intensity of pain
• Enhancing physical functioning
• Improving psychological functioning
• Promoting return to work or school and/or role within family and society
• Improving health-related quality of life
Ibuprofen is the most frequently used OTC analgesic in Europe. 5 A Cochrane review investigating the effects of analgesics/analgesic combinations (given as single doses postoperatively) concluded that there is evidence supporting the efficacy of these OTC drugs that are available without prescription, with ADRs generally not different from placebo. 6 There are risks associated with OTC NSAID intake in certain groups such as pregnant women, older people, and people taking additional medications although data suggests overall that the risk of severe ADRs from OTC analgesics remains low. Improving safety relies on increasing consumer awareness of risks, which is done by pharmacists, pharmacy technicians and OTC staff on a daily basis. 5
Over-the-Counter Analgesia and Evidence
A review of the comparative effectiveness of opioid, nonopioid pharmacologic, and non pharmacologic therapy in acute pain conditions was conducted. Opioid therapy was associated with decreased or similar effectiveness as an NSAID for some acute pain conditions, but with increased risk of shortterm adverse events. 7 Evidence on nonpharmacological therapies was limited, but heat therapy, spinal manipulation, massage, acupuncture, acupressure, a cervical collar, and exercise were effective for specific acute pain conditions. Authors of a separate Cochrane review on the efficacy of OTC analgesics in acute pain made the following observations. 6
• There was evidence to show that simple, inexpensive, readily available analgesics give good pain relief to many patients with acute pain, such as toothache, sprains and strains.
• The most effective OTC drugs used were ibuprofen/ paracetamol combinations in 400mg/1,000mg and 200mg/500mg doses; respectively, providing relief to 70% of people, and with a NNT of less than 2.
• Fast acting ibuprofen formulations were effective in over 50% of patients, with a NNT of 2 to 3.
• Paracetamol alone helped about 40% of patients and had a NNT of between 3 and 5, which was dose dependent.
• Of particular note was an absence of evidence to support efficacy of low-dose codeine preparations in acute pain.
• The authors also question the standard advice supplied with ibuprofen and other NSAIDs to take them with food: the absorption of these drugs is faster on having an empty stomach which increases efficacy. Some ibuprofen product PILs have in fact been changed to reflect this advice
In a Cochrane review specifically looking at the efficacy of topical NSAIDs for musculoskeletal conditions, authors found that. 8
• Topical NSAIDs provided good levels of pain relief in acute conditions such as sprains, strains and overuse injuries, probably similar to that provided by oral NSAIDs.
• Formulations of topical diclofenac, ibuprofen, and ketoprofen in particular demonstrated significantly higher rates of clinical success (more participants with at least 50% pain relief) than matching topical placebo.
• For diclofenac, the Emulgel formulation had the lowest NNT of 1.8 for at least 50%
pain intensity reduction. Diclofenac plasters (except fhr the brand Flector) also had a low NNT of 3.2.
• Ketoprofen gel had an NNT of 2.5 (but less well defined outcomes).
• Ibuprofen gel had an NNT of 3.9 as measured by outcomes of marked improvement or complete remission.
• Data was insufficient to make comparisons between individual topical NSAIDs or against the same oral NSAID.
• Local skin reactions were generally mild and transient, and did not differ from placebo, and very few systemic adverse events.
Notably, etofenamate topical preparations were not included in this review.
In terms of specific nonpharmacological approaches, review authors 7 found that heat therapy was probably associated with moderate decrease in pain compared to usual care or placebo, particularly for lower back pain. Further evidence for the use of non-pharmacological measures in this review were not robust enough to make recommendations, however.
Non-Steroidal Anti-inflammatories
Ibuprofen is the first line treatment recommendation for a range of aches and pains including lower back pain, period pain and toothaches. Although aspirin can also be used for many aches and pains, other NSAIDs like ibuprofen tend to be better tolerated, so are the preferred option. 3 Non-steroidal anti-inflammatory drugs work through mediation of prostaglandin and thromboxane A2 production through reversible inhibition of the enzyme cyclooxygenase (COX). Prostaglandins mediate many physiological functions including inflammatory and nociceptive processes; also maintaining the gastric mucosal barrier, regulating renal blood flow and endothelial tone. 6 These medicines should not be taken in people with active gastrointestinal bleeding/ulcers, previous hypersensitivity to NSAIDs, severe heart failure, or severe liver or kidney impairment. 3
Paracetamol
This is a great first line choice for mild to moderate pain. It has no known GI, renal or cardiac adverse effects at the usual OTC and prescribed doses; however, the patient should be reminded of the maximum daily dose over 24 hours to reduce the risk of accidentally exceeding this. Paracetamol appears to inhibit COX 1 and COX 2, although it does not inhibit COX in peripheral tissues. It is for this reason that paracetamol has no peripheral anti-inflammatory effects like traditional NSAIDs. 9
Codeine
Codeine and paracetamol combination products should only be offered for e.g. managing acute lower back pain if an NSAID is not suitable or has been ineffective. 3 Opioids are not suitable to recommend for acute treatment of tension type headaches or migraines. Tolerance and dependence can occur with use of weak opioids, so caution should be used. The codeine and paracetamol OTC products are not suitable in acute ulcerative colitis, or conditions that may include abdominal distension or inhibition of peristalsis as a symptom. Peripheral receptor binding can cause nausea, vomiting and constipation. 6
Caffeine
Caffeine does not have any painrelieving effect itself, but rather is added as an adjuvant to ibuprofen, aspirin and/or paracetamol products to enhance their analgesic effects. It is a competitive antagonist of adenosine A1 and A2 receptors, so it is possibly the disruption of normal adenosine signalling responsible for any enhanced analgesia. 10
Pain Management Guidelines
There are no specific clinical guidelines that provide information on how to manage acute pain with OTC analgesics, but there are a few available that are still relevant such as the NICE management of acute postoperative pain, and several indication specific guidelines for e.g headache, back pain, dysmenorrhoea, and sprains and strains. 3 These guidelines should be considered along with the ever changing evidence base, particularly important if there is a few years since the guidelines were updated.
The WHO analgesic ladder, published in 1986, provided guidance on how to provide adequate pain relief in cancer. It has gone through several modifications since its initial appearance, and is now used for the treatment of pain in additional types of conditions like degenerative disorders, musculoskeletal diseases, neuropathic pain, and other types of chronic pain. 11 The original version was unidirectional, starting with NSAIDs or paracetamol as step 1, and heading up to weak (step 2) and strong (step 3) opioids, with or without adjuvants, depending on the patient’s level of pain. It has been suggested that step 2, which recommends the use of weak opioids, be eliminated, as there is little evidence that these offer much for pain control. Instead, reduced doses of strong opioids may be more useful. However, opioids aside, one main limitation of the original pain ladder was lack of inclusion of non-pharmacological approaches into the pain treatment path. Subsequently, a fourth step has been added to the pain ladder. This integrates non-pharmacological evidence based interventions like epidural anaesthesia, intrathecal administration of analgesia, neurosurgical procedures, neuromodulation strategies, nerve blocks, and ablative procedures (the removal or destruction of a body part or tissue or its function),
among others. There is more of a focus on quality of life with the updated WHO pain ladder, with a bidirectionality that offers de-escalation if pain improves as well as stepwise escalation for worsening pain. Some of the main elements are:
• Oral dosing of drugs whenever possible
• Around-the-clock administration for pain control rather than on-demand
• Analgesics must be prescribed according to pain intensity as evaluated by a scale of pain severity. For this purpose, a clinical examination must combine with an adequate assessment of the pain.
• Individualised therapy (including dosing) addresses the concerns of the patient. This method presupposes that there is no standard dosage in the treatment of pain, maybe the biggest challenge in pain management, as the dose must be continuously adapted to the patient, balancing analgesic effects with potential side effects.
• Proper adherence to pain medications, as alteration in the dosing can lead to a recurrence of pain.
With evidence that pharmacistled management of pain helps to optimise outcomes in selfmedicating people, pharmacy teams have a very important role in the acute management of pain. Using up to date research evidence and guidelines can help pharmacy teams with the provision of the most effective treatment strategies. Advice on appropriate OTC analgesia tailored to each patient, considering age, medical conditions and other medications can be offered, as well as advice about topical vs. oral administration. Appropriate referral to a GP for stronger medication can be made if necessary.
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