Pain Systems II: Pharmacology And Management
The development of pain is a common experience and the treatment for it is important, not only where it is caused by injury or inflammation, but also in cases where the nerves themselves are damaged. In these latter cases the pain can arise from a site of previous injury (e.g. allodynia) or may develop for more obscure reasons, now renamed complex regional pain syndrome. In all cases, pain is both disabling and depressing, and a multidisciplinary approach to management is often needed. However, it should also be realized that some patients with affective disorders, such as depression and anxiety, may complain of pain in the absence of any obvious tissue damage.
Management of pain
Pain relief or analgesia can be approached using a number of different strategies.
Many analgesic therapies work by reducing the peripheral inflammatory response, which is also responsible for receptor sensitization (site I on figure). Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesics. These drugs have analgesic, antipyretic and, at higher doses, anti-inflammatory actions. Aspirin was the first NSAID but has been largely replaced by drugs that are less toxic to the gastrointestinal tract, e.g. paracetamol, ibuprofen, naproxen. NSAIDs produce their effects by inhibiting cyclo-oxygenase (COX), a key enzyme in the production of prostaglandins (PGs). PGs are one of the mediators released at sites of inflammation. They do not themselves cause pain but they potentiate the pain caused by other mediators, e.g. bradykinin, 5-hydroxytryptamine (5-HT), histamine (site I on figure).
NSAIDs are not effective in the treatment of visceral pain, which usually requires opioid analgesics.
The interruption of peripheral nerve conduction by injection of local anaesthetics can be helpful in some pain states, but lesioning of the peripheral nerve is usually without effect in ameliorating neuropathic pain (site II), unless it is to remove a neuroma.
This site involves blocking aberrant sympathetic innervation/activation of peripheral nociceptors as occurs in some patients in response to nerve/limb injury (see below).
The organization of the nociceptive input to the dorsal horn has been explored clinically in pain management. For example, stimulation of non-nociceptive receptors can inhibit the transmission of nociceptive information in the dorsal horn, which means that painful stimuli can be ‘gated’ out by counter-irritation using non- painful stimuli. This is the basis of the gate theory of Wall and Melzack and is exploited clinically in the use of transcutaneous nerve stimulation (TENS) in areas of pain (site VI), as well as the stimulation of the dorsal columns themselves in some cases of chronic pain (site V).
Similarly, the supraspinal input can also gate out noxious stimuli when activated (site VII), as occurs in stressful situations, when attending to a painful stimulus would not necessarily be useful (e.g. war injuries). These supraspinal nuclei can also be manipulated pharmacologically, with the administration of drugs that are usually used in the treatment of depression (see Chapter 57). These antidepressant drugs with a presumed action at the noradrenergic and serotoninergic synapses have been used to treat pain states, irrespective of any antidepressant action they might have (site VII). The most commonly used agents are amine uptake inhibitors, such as imipramine and amitriptyline (tricyclic antidepressants). These agents appear to alter the pain threshold but are not without side effects (see Chapter 57).
Furthermore, the recognition that one of the major transmitters in the nociceptive pathway is substance P (SP) has led to the development of other analgesic medications. For example, capsaicin (the active ingredient of red chilli), which initially releases SP from nociceptors and subsequently inactivates the SP-containing C fibres, can be used topically in some pain syndromes such as post- herpetic neuralgia. However, perhaps the most common exploitation of this system is the manipulation of the enkephalinergic interneurone and opioid receptors by the exogenous administration of morphine and its analogues to control pain (site IV).
Opioid analgesics are drugs that mimic endogenous opioid pep- tides by causing a prolonged activation of opioid receptors (usually μ-receptors). This reduces pain transmission at synapses in the dorsal horn of the spinal cord by an inhibitory action on the relay neurones. Opioids also stimulate noradrenergic, serotoninergic and enkephalinergic neurones in the brainstem that descend in the spinal cord and further inhibit the relay neurones of the spinothalamic tract. Opioid analgesics are widely used to relieve dull, poorly localized (visceral) pain. Repeated doses can cause dependence so that the sudden termination of opioid analgesics may precipitate a withdrawal syndrome.
• Morphine is the most widely used analgesic in severe pain but, like all strong opioids, may cause nausea and vomiting.
• Diamorphine (heroin) is more lipid soluble than morphine and therefore has a more rapid onset of action when given by injection and is widely used for postoperative pain.
• Fentanyl can be given transdermally in patients with chronic stabilized pain. The patches are very useful in patients with intractable nausea or vomiting when taking oral opioids.
• Methadone has a long duration of action and is less sedative than morphine. It is given orally for the maintenance treatment of heroin or morphine addicts. The methadone prevents the ‘buzz’ of intravenous drugs and so reduces the point of taking them.
• Buprenorphine is a partial agonist at the μ-receptors. It has a slow onset of action. It has a much longer duration of action than morphine (6–8 hours), but may cause prolonged vomiting.
• Tramadol is a weak μ-agonist and its analgesic action is mainly a result of enhanced serotoninergic neurotransmission.
• Codeine and dextropropoxyphene are weaker drugs used in mild to moderate pain.
• Naloxone is an antagonist at opioid receptors and is used to reverse the effects of opioid overdose.
Although pain typically arises from tissue damage, it can also occur with damage to the peripheral and central nervous systems. One such example is trigeminal neuralgia (see Chapter 50). It can be treated surgically by lesioning of the appropriate nerve root, although most patients respond to the antiepileptic agent carbamazepine or gabapentin (see Chapter 61).
More recently there has been interest in using deep brain stimulation for managing some patients with chronic pain. Whether this works or not is currently unresolved. The main targets for the stimulator are motor cortical areas for reasons that are not clear.