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.
Site I
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.
Site II
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.
Site III
This site involves blocking aberrant
sympathetic innervation/activation of peripheral nociceptors as occurs in some
patients in response to nerve/limb injury (see below).
Sites IV–VII
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.
