Pharmacology in Pain Management

Original Editor - Eve Jenner

Top Contributors - Eve Jenner, Tarina van der Stockt, Jo Etherton, Michelle Lee and Tony Lowe  

Introduction

A wide range of drugs is used to manage pain resulting from inflammation in response to tissue damage, chemical agents/pathogens (nociceptive pain) or nerve damage (neuropathic pain). Most drugs act by binding to protein targets on cell membranes and affecting the biochemical processes of the body. Protein targets are specific to specific tissues allowing drugs to be precisely targeted at individual organs or cells. Drugs exhibiting high specificity require lower doses and have fewer side effects than those with lower specificity.[1]

WHO Analgesic Ladder Step 1-3

Originally developed by the World Health Organisation (WHO) to improve management of cancer pain; the 3 step WHO analgesic ladder is also used for providing stepwise pain relief for pain due to other causes.

Non-opioid medications: (step 1 WHO Analgesic ladder – mild to moderate pain.[2] 

  • Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, diclofenac weaken and reduce the levels of chemical mediators (prostaglandins) produced during inflammation, relieving symptoms of pain, swelling and redness. They inhibit the enzyme cyclo-oxygenase (COX 2) which is integral in the synthesis of prostaglandins. During infection, the effect of prostaglandins on the hypothalamus results in a higher body temperature (pyrexia). NSAIDs weaken the production of prostaglandins enabling the temperature to reduce towards normal. NSAIDs do not just inhibit local prostaglandin production, but also throughout the body, producing side effects in other body tissues/systems such as the gastrointestinal tract (GIT). GIT side effects are explained by NSAIDs interference with the normal homeostasis role of prostaglandins (mediated by COX 1 enzyme) in maintaining gastric mucosa and regulating stomach acids.[1] Side effects affecting GIT may include indigestion, nausea and vomiting, and diarrhoea and can result in ulceration and bleeding. Other side effects include rashes, photosensitivity, bronchospasm, dizziness and haematuria.[3] NSAIDs must be used with caution in the elderly, and people with diabetes, asthma and impaired renal or cardiac function.[3] NSAIDs are contraindicated for people with a previous history of adverse reaction, a history of peptic ulcer or clotting disorders and those taking anticoagulants or another NSAID medication.[3]
  • Paracetamol also known as acetaminophen. Although it is the most widely used pain relieving medication the exact mechanism of action of paracetamol is relatively poorly understood. It is thought to act on the COX 3, a recently discovered type of COX present in the brain and spinal cord. Paracetamol has mainly anti-pyretic (reducing the levels of prostaglandins in the hypothalamus) and analgesic properties; it does not interfere with COX 2 and does not affect the other components of inflammation (swelling and redness). As paracetamol has no action on COX 1 at a therapeutic dose it has few side effects.[1] The maximum recommended daily therapeutic dose of paracetamol for adults is 4g (8 x500mg tablets). It is hepatotoxic at only 2-3 times the therapeutic dose causing necrosis of the liver and resulting in 226 deaths in 2013 in England and Wales [4]
  • Aspirin also known as acetylsalicylic acid (ASA). Thromboxanes are inflammatory mediators derived from platelets that cause vasoconstriction and aggregation of platelets leading to clotting. Aspirin inhibits the production of COX 2 enzymes, which are also essential to the production of thromboxanes, inhibiting platelet aggregation and clots leading to its use in the treatment and prophylaxis of cardiovascular disease or myocardial infarction.[1] 


Compound analgesics: (Step 2 on the WHO analgesic ladder – mild to moderate pain[2])

Compound analgesics are a combination of drugs in a single tablet usually including codeine (a weak opiate) and aspirin or paracetamol. Examples include co-codamol and co-dydramol which contain codeine and paracetamol in various formulas (8/500, 10/500, 15/500, 30/500) where the first number refers to the amount of codeine and the second to paracetamol.
Co-codaprin is a combination of codeine phosphate (8mg) with aspirin (400mg).
Tramaset contains a low dose (37.5mg) of the strong opioid tramadol combined with a reduced dose of paracetamol (325mg).[3]

Compound analgesics may be used on their own or in combination with NSAIDs (such as ibuprofen). NSAIDs, paracetamol and opioids decrease pain via different mechanisms so used together can improve pain relief.[2]
Some low dose compound analgesics may be purchased over-the-counter (OTC) but most require a prescription.
Medications containing codeine may cause side effects including nausea, vomiting, constipation and drowsiness[3] with particular implications for people who need to drive or operate machinery as part of their day to day role.

Opioid medications (Step 3 on the WHO analgesic ladder – severe pain[2])

Medications derived from morphine (or synthetic analogs)  mimic the body’s own analgesic system and are strongest and most effective painkillers currently available.[3] They have a similar molecular structure as endogenous opioids (β-endorphine , dynorphin and enkephalins) and produce the same effect. They work in the central nervous system by binding to opioid receptors in the pre- and post-synaptic membrane stopping the passage of neurotransmitters across the nerve synapse which blocks or attenuates the experience of pain.

Opioid medications include morphine, oxycodone, codeine, tramadol, buprenorphine, fentanyl and diamorphine (heroin).[3]  In people with chronic pain opioid medications may be given orally ( as a capsule, tablet or liquid)  or via a patch (transdermal). With either route slow or modified release preparations are often used to minimise fluctuations in pain relief and reduce the number of tablets that need to be administered. Modified / slow release medication also avoids people 'clockwatching' for the next dose. Examples of slow or modified release medicines which work over 12 or 24hrs include tramadol preparations such as Zydol or Zamadol[3]. Fentanyl and Buprenorphine may be administered via transdermal patches which are applied every few days. 

Opioid receptors are present in tissues throughout the body and the interaction of the drugs with these receptors is responsible for the side effects associated with opioid medications. In the GIT these include nausea and vomiting and, as a result of decreased gut motility, constipation. Opioids also reduce the sensitivity of the respiratory centres in the brain stem to CO2 leading to respiratory depression. Other effects include drowsiness and dizziness and prolonged use can lead to hormonal changes which can lead to reduced libido, infertility and depression [5].[6][1]Accidental overdose is a significant risk; the drug naloxone is used to reverse the effects of opioids and is used to treat a narcotic overdose.[3]   To avoid withdrawal symptoms opioid medications should be reduced slowly under medical guidance and not stopped abruptly[5] 

The use of opioids for chronic non-cancer pain is controversial. Pain is rarely abolished and the use of analgesia is to enable the individual to participate in rehabilitation to restore function and maximise quality of life.[5] Prolonged use of opioids can result in tolerance (where an increased dose of a drug is required to produce the same analgesic effect), psychological dependence and sometimes addiction and abuse. There is evidence that people with chronic pain may not benefit from opioid use. People who use opioids for a prolonged time may develop hyperalgesia which is distinct from their original pain problem and may present as a more diffuse less defined pain[5] A Danish study reported significant associations between opioid use and an increase in moderate to severe pain as well as a reduction in quality of life scores and poorer self-rated health in people with chronic pain taking opioid medication versus those who were not. Using opioids was also linked to low levels of exercise, unemployment and higher health care usage.[7]  The Cochrane review [8] found that there was no statistically significant difference in pain relief and functional improvement between strong opioids and NSAIDs for people with chronic low back pain. 

Adjuvants

The WHO analgesic ladder[2] recommends that patients are prescribed additional medication to manage the symptoms of neuropathic pain resulting from post hepatic neuralgia, phantom limb pain, peripheral neuropathy and pain caused by nerve compression e.g. severe sciatic pain, when these symptoms are not responding.[2] These drugs include tricyclic antidepressants and antiepileptic drugs target proteins (neurotransmitters) within the cell membrane of the CNS. Because of their dual role, it is important that patients understand that they are prescribed these medications to control of troublesome pain symptoms rather than because of epilepsy or a mental health condition. NICE Guidelines CG173 recommends offering a choice of Amitriptyline, Gabapentin, Pregabalin or Duloxetine as initial treatment for neuropathic pain changing to another drug if the first is ineffective or poorly tolerated.[9] More than one of these drugs should not be prescribed concurrently.[9] Evidence cited by NICE suggests that compared to placebo these drugs had a significant effect on the symptoms of neuropathic pain.[10] Although these medications are helpful and well tolerated by many people they can produce significant side effects which may result in people needing an alternative medication or declining this group of drugs.

  • Amitriptyline: Tricyclic antidepressant. Acts by blocking the reuptake of the neurotransmitters noradrenaline and serotonin (5-hydroxytryptamine ) in the CNS potentiating their effect.[11] Although it is widely prescribed Amitriptyline is not currently licensed for the treatment for chronic non-malignant pain (off-label)[11] Amitriptyline exhibits strong anticholinergic activity affecting the parasympathetic nervous system which may limit its prescription and can result in a range of side effects.Contraindications include cardiac arrhythmias, severe liver disease, and in the acute phase of MI. Common side effects include dizziness, drowsiness, dry mouth, nausea and constipation. Patients taking Amitriptyline should be warned about potential problems with driving or operating machinery.
    Amitriptyline interacts with a large number of other medications which may preclude its prescription for people with co-morbidities [12]
    Physiotherapist Independent prescribers should only prescribe ‘off-label’ where it is best practice to do so or where there is a body of opinion to support off-label use.[13]
  • Gabapentin (Neurontin) Anticonvulsant used for treating epilepsy but also licensed for use for managing neuropathic pain. Damage or disturbance to the function of the cell can produce an increase in the excitability of the nerve cell. The exact mode of action is not understood but Gabapentin is thought to work by binding to the Calcium channels in nerve cell membranes in the CNS. This reduces the Ca ions flowing into the nerve terminals and inhibits the release of the excitatory neurotransmitter ‘glutamate’ reducing the nerve cell excitability and this can decrease the symptoms of chronic pain and fibromyalgia [14] Common side effects include drowsiness and dizziness but these usually decrease over time. Other side effects include tiredness, weight gain, headache, difficulty with vision, tremor, numbness, loss of appetite, nausea or vomiting. Gabapentin has few interactions with other medicines making it suitable for patients taking medication for other conditions.[15]
  • Pregabalin (Lyrica). Anticonvulsant indicated for use in chronic pain, especially neuropathic pain and fibromyalgia. Pregabalin is thought to act by binding to α2δ receptors which inhibit the calcium (Ca) channel and reducing Ca ions flowing into the nerve terminals decreasing the release of neurotransmitters ( glutamate, nor adrenaline and substance P). Pregabalin increases the neuronal levels of the inhibitory neurotransmitter GABA by increasing the enzyme (glutamic acid decarboxylase) that converts the excitatory neurotransmitter glutamate to GABA  and evidence suggests that this can result in significant reduction in neuropathic pain and improvement in associated problems such as sleep and anxiety [16] Pregabalin is contra-indicated in breastfeeding and has to used with caution in severe congestive heart failure, renal impairment and pregnancy. It should not be stopped abruptly; the dose should be decreased gradually.  Dizziness and drowsiness are very common (>10%) side effects and between 1-10% of users may experience visual disturbance, ataxia, tremor, lethargy, impaired memory, euphoria, weight gain, decreased libido, erectile dysfunction, constipation, dry mouth or dysarthria. Infrequent (0.1-1%) side effects include depression, confusion and hallucinations.
    Pregabalin has few interactions with other medicines making it suitable for patients taking medication for other conditions[17]
  • Duloxetine. (Cymbalta) A serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant. SNRI’s block or delay the reuptake of the neurotransmitters, serotonin and noradrenalin increasing the level of these neurotransmitters in the synapse. Changing the chemical balance within these pathways affects the perception of pain and has a positive effect on an individual’s wellbeing.[18] Duloxetine has been shown to be an effective treatment for painful neuropathy, chronic pain and fibromyalgia.[19] [20] Dry mouth, headaches, nausea, dizziness and drowsiness are very common side effects (>10%). 1-10% of users may experience side effects including constipation or diarrhoea, problems with sexual function, muscle and bone pain, tremor and muscle spasm. There are a large number of less common side effects.[21] Duloxetine interacts with a wide range of common medications which may limit its use in individuals with co-morbidities.[22]

Topical analgesics

Topical analgesics can provide localised pain relief. They have low levels of systemic absorption which reduces the risk of side effects and limits interactions with other medications[23]

Topical analgesics include rubefacients, topical NSAIDs and local anaesthetics.[24]   

Rubifactants include a wide range of gels and creams; some are available over the counter (OTC) and others require a prescription (PoM). They are thought to provide a counter-irritant effect by stimulating the sensory nerve endings and altering the pain in tissue ( muscle and joints) innervated by the same nerve. They also cause skin reddening and produce a comforting warmth.

Topical capsicum may be prescribed for chronic pain conditions such as post herpatic neuralgia and diabetic neuropathy. It is formulated either as a cream (0.075%) or as an 8% concentration patch. The cream is licenced for the treatment of postherpatic neuralgia and diabetic neuropathy and the patch for peripheral neuropathic pain in non-diabetic patients[25]. The patch has been shown to be more effective than the cream  (NNT's of 8.8 and 7.0 respectively).[26]   The active ingredient that produces the heat in chilli peppers capsaicin binds to nociceptors in the skin increasing sensitivity to noxious stimuli. Initial sensations of burning, tingling or itching are followed by a refractory period of decreased sensitivity and multiple applications can result in sustained desensitisation and relief from pain.[27]  Capsicum has been shown to be more effective than placebo in people who have chronic soft tissue pain.[28]  There is some evidence of benefit for people with chronic low back pain. [29]

Topical NSAIDs ( including ibuprofen, naproxen and diclofenac ) are used in acute and chronic pain conditions. They are considered as an adjuvant treatment for arthritis of the knee and hand. Most topical NSAIDs are available as PoM but some of the weaker formulations may be purchased OTC [25] A recent Cochrane review supports the use of topical NSAIDs for the management of knee and hand arthritis but can find no evidence for their use in other chronic pain conditions [30].

Topical local anaesthetic for example lignocaine patch can be used in chronic pain states such as post-hepatic neuralgia, chronic low back pain and complex regional pain syndrome (CRPS).  The efficacy of lignocaine patches is disputed; a recent systematic review concludes that although some studies and patients report benefit overall there is no evidence to support the use of lignocaine patches for the treatment of neuropathic pain [31]

Local anaesthetics

Systemic local anaesthetics such as intravenous lignocaine may be used to treat chronic neuropathic pain conditions including fibromyalgia. These drugs act as sodium channel blockers. Sodium channels are thought to be only present in peripheral nerves. When nerves are damaged or irritated excitability and spontaneous firing increases mediated by the increased flow of sodium ions across the cell membrane. Sodium channel blockers slow or stop the flow of ions reducing the excitability of the cell and producing a decrease in the sensation of pain. Sodium channel blockers are also thought to have an effect on glutamate production in the dorsal horn  reducing nerve cell activity [32] 

Research suggests that these drugs may be effective in reducing pain due to nerve damage [33]

Trigger point injections of local anaesthetic and steroid may also be used to treat myofascial pain and conditions including headache . The mechanism of action is unclear and there is no clear evidence of benefit in chronic musculoskeletal pain [34] 

Limitations of the pharmacological management

People with persistent pain benefit from a biopsychosocial approach which addresses their thoughts and feelings about their condition combined with a programme to increase levels of activity and promote self-management. It is important to understand the limitations of the pharmacological management of chronic pain, the importance of combining pharmacological approaches with non-pharmacological management of chronic pain and the use of such strategies alongside appropriate evidence-based active self-management strategies.

References

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