Current drug treatment

The classical treatment of pain involves both direct and indirect approaches: direct approaches decrease the activation of pain neurons, while indirect approaches work more to attenuate the source of continued pain, the inflammation.

Drugs acting directly on pain-associated nerves

Morphine-like opioids are used to directly treat pain. It is thought that they do this via one of two mechanisms at both peripheral and central locations:

1) they prevent the generation of action potentials in peripheral afferent nociceptive neurons and spinal transmission neurons by hyperpolarisation. They do this by opening K+ channels via protein kinase A
2) they directly stimulate the centrally-located periaqueductal grey, which in turn inhibits pain sensation by the descending control pathways.

In addition, they are known to work on the limbic lobe of the brain (the emotional centre), generating a state of euphoria that helps a patient deal with the affective aspect of pain. One final application, that is currently hotly disputed, is that morphine appears to inhibit the generation of substance P, usually key in sensitising the spinal neurons to pain.

There are many opioid drugs around today, all of which are either analogues (become morphine once broken down in the body) or derivatives (similarly-structured molecules that are agonists at morphine receptors) of morphine. Most of these drugs act at the μ-opioid receptor. There are many side-effects associated with morphine-like opioids: respiratory depression, cough reflex depression, nausea, vomiting and most importantly, physical and psychological addiction. Different opioids show different side-effects, and so are appropriate in different situations. Some key drugs used in analgesia are detailed below, with their relative advantages/ disadvantages and applications:

Diamorphine (heroin) More rapidly crosses the blood-brain barrier and so useful for strong acute pain Highly addictive
 

Codeine Milder form and not addictive, so can be used for minor injury pain 10% of people lack the demethylase enzyme required to break it down to morphine, so doesn’t always work
 

Pentazocine Just as potent as morphine, but less addictive (supposedly since increasing dosage does not increase effect) Still addictive
 

Meptazinol No respiratory depression and short lasting, and so useful in pregnant women Still addictive, may harm baby.

Drugs used to indirectly reduce pain

The indirect treatment of pain involves the usage of non-steroidal anti-inflammatory drugs (NSAIDs). These drugs work to attenuate the inflammatory response seen at the site of injury, and to reduce the sensitisation of pain neurons by the inflamed environment. They do this by inhibiting the Cyclo-oxygenase 2 enzyme responsible for the conversion of arachidonic acid to prostaglandins.

Inhibition of PGI2 and PGE2 removes the sensitisation of C-fibre neurons to Bradykinin, and inhibition of other prostaglandins reduces the inflammation itself. Inhibition of one particular prostaglandin PGD2 (a vasodilator), is thought to be the reason why NSAIDs can treat vascular headaches.
Several NSAIDs are used clinically to reduce inflammation and thus provide analgesia, each of which having its own pros and cons. The majority of NSAIDs have the diadvantage they do not selectively inhibit COX2, but may also inhibit COX1 and COX3.

Aspirin (acetylsalicylic acid) is the oldest of them all, and was discovered hundreds of years ago by tribal men from the bark of the willow tree. Aspirin works to inhibit COX1/2 and so is effective at analgesia, but because of the additional inhibition of COX1 may have unwanted side-effects in the gastrointestinal tract. This can overcome in patients having chronic treatment by prostaglandin “supplements” of misoprostol.

Ibuprofen works in a similar way to aspirin, being different in that it has fewer side-effects in some people.

Paracetamol, the most commonly self-administered analgesic worldwide, appears to act on COX3 to generate analgesia, and doesn’t appear to affect inflammation at all (this is disputed).

Finally, more recent drugs have been developed that are COX2 specific and so have fewer side-effects: Celecoxib and Rofecoxib are good examples.

For chronic treatment of inflammatory pain, Naproxen is often prescribed.

 Summary diagram: sites of action of direct/indirect  analgesics on the dendrites of primary afferent nociceptive neurons

Treatment of neuropathic pain

All of the drugs mentioned thus far work to attenuate the nociceptive aspect of pain- the basic signals that alert us to the presence of noxious stimuli/ tissue damage. However, in the case of neuropathic pain, where damage has been done to neurons by conditions such as multiple sclerosis, diabetic neuropathy, herpes zoster infection, traditional analgesics have proven to be ineffective.
There is hope however- the careful observation of clinicians has revealed that unconventional drugs used to treat different disorders appear to have analgesic effects for neuropathic pain. Anticonvulsants such as carbamazepine and gabapentin are sometimes useful in neuropathic pain analgesia. This suggests that sometimes this type of pain may result from spontaneous action potential firing in damaged nerves- a fact that is further backed by the observation that intravenous lidocaine (an anaesthetic) is also useful in treatment of chronic neuropathic pain.
Tricyclic antidepressants such as imipramine and amitriptyline also appear to reduce neuropathic pain. This effect is likely independent of their antidepressant effects since other affective disorder treatments such as specific serotonin reuptake inhibitors (SSRIs) have proven useless in analgesia of neuropathic pain.
In any case, the mechanisms by which neuropathic pain may be treated are still under investigation.

Treatment of severe spinal cord pain

Alongside the standard morphine-like opioids and NSAIDs, patients suffering from chronic back pain may be offered a radical alternative : Epidural (corticosteroid) administration. While epidurals seem effective in the short term, as reviewed by Salahadin A et al, the evidence for long-term spinal pain treatment is varied. Evidence for the usefulness of epidurals in cervical and caudal spinal pain is “moderate”, while there is still “limited” evidence for the usefulness of epidurals in long-term lumbar back pain.
The mechanisms by which these epidural injections work are thought to be similar to the previously described drugs, although the full mechanisms remain to be elucidated.
 

Notice: diagrams

All diagrams on this website are my own, generated using Microsoft Powerpoint and Paint.