Pain is the body's most important defence mechanism. It also results from disease. A lot of specialised research is under way to develop new pain-killers and to improve those that we already have. The prospects for people in pain should significantly improve in years to come.

What is pain? Top

From the earliest times, mankind has been stalked by the spectre of pain and there is much evidence from early civilisations of the struggle to provide pain relief. Over the millennia, pain has been variously attributed to demons, evil humours or dead spirits, or seen as a punishment for wickedness – in fact, the word “pain” derives from the Latin word “poena”, for punishment.

Under normal circumstances, acute pain is a defence mechanism - a warning to the body that something is going wrong or that there is a risk of injury. Rare individuals born without a sense of pain usually have short lives and many injuries, because they have no warning mechanism. Chronic pain, however, serves no such purpose. Chronic pain may result from direct tissue injury and inflammation (e.g. arthritic musculoskeletal pain), from disease-related damage, or from the nervous system itself (neuropathic pain), for example, in diseases such as diabetes.

Who does pain affect? Top

Nearly two-thirds of adults in the EU experience back pain at some time in their lives and 35 million people a year consult their GP because of it. Further, chronic pain is a common feature of the later stages of diseases such as osteoarthritis, rheumatoid arthritis, osteoporosis, diabetes and cancer, and can lead to major disability; little surprise that pain has been called the “silent epidemic”.





Figure 1: The human brain in cross section, showing many of the structures concerned with pain processing and perception.

Present treatments Top

Modern management of chronic pain seeks to eliminate pain completely where possible and to establish a treatment schedule consistent with the minimum use of medication that prevents it recurring, rather than allowing it to return and then re-treating active pain.

There are three distinct elements in pain: detection by receptors, transmission by the nerves, and the perception/interpretation by the brain. Accordingly, the wide range of medicines that are used in pain management act at a variety of sites in the body. Some act in the peripheral tissues at the site of damage. Others act in the spinal cord, while yet others act in the brain. For example, a synthetic version of a peptide found naturally in snail venom which blocks N-type calcium channels has been developed for treatment of severe chronic neuropathic pain. The medicine is applied by using a subcutaneous pump.

Another interesting approach has been the development of pain-relieving preparations based on cannabinoids. Delivered as a spray, one (tetrahydrocannabinol) is used in patients with cancer pain, while another (a tetrahydrocannabinol: cannabidiol combination) has been shown to be effective in pain from spinal cord injury and in neurogenic pain.

Therapy often needs to be individualised, but pain management generally follows the three-step ‘analgesic ladder’ established by the World Health Organisation in 1990. This entails first using non-opioid analgesics or non-steroidal anti-inflammatory drugs (NSAIDs). If this proves inadequate, a weak opioid is added or substituted. In addition, steroids, local anaesthetics, anti-emetics or tranquillisers may be given to increase the effectiveness of these analgesics.

Lastly, in severe, intractable pain, strong opioids are used. These include transdermal patches of opioids and slow release morphine, which give a more even and prolonged effect than some injected or oral treatments. Despite these alternatives, many people suffer from intractable chronic pain or neuropathic pain that is difficult to control, or experience breakthrough pain as the effect of their medicine wears off.

What’s in the development pipeline? Top

Medicines research into pain is very specialised and many analgesics are already available, but there are a considerable number of companies actively working in this area. The sensation of pain is complex and this gives considerable scope for developing medicines that act by new mechanisms, or on different parts of the nervous system.

One example of such a mechanism involves exploration of the ability of adenosine to modulate pain perception. Several research groups have shown that the adenosine A1 receptor, known to be important in nerve transmission, is involved in neurogenic pain, and adenosine itself (which occurs naturally in the body) has analgesic properties. Several modulators of this receptor are in Phase 3 trials for effectiveness in treating neuropathic pain. Other agents under development act on nerve pathways involving glutamate. This includes the N-methyldiamino-aspartate (NMDA) receptor, a particular part of which is thought to be involved in the maintenance of chronic pain. Another approach to treating neuropathic and chronic pain is to act on neuronal receptors responding to the neurotransmitter acetylcholine.

While not involving a new mechanism, NSAIDs with a lower incidence of side effects are also being studied. Research is underway with an unusual COX-2 inhibitor that delivers nitric oxide to sites of inflammation. Nitric oxide is known to have relaxing actions on the muscles of capillary walls that result in reduced inflammation.

New types and formulations of opioids are also being developed. The efficacy of an opioid transdermal patch, currently approved for cancer-related pain, is being studied in a Phase 3 trial in chronic back pain. The patch delivers the medicine over 72 hours. Another research group is developing the new synthetic opiate fumarate for moderate to severe pain, which is in Phase 3 trial.

Meanwhile, scientists are ringing the changes on morphine itself, with a sustained release form (Phase 3 in post-operative pain), and the metabolite morphine-6-glucuronide, which has fewer unwanted effects than the parent compound is also in Phase 3 for relief of pain after hip replacement.

At the late stage of clinical development is a compound with a dual mechanism of action. It combines the properties of an agonist of the μ-opioid receptor and a noradrenalin-reuptake inhibitor. By binding to the μ-opioid receptor in the brain the medicine influences the central nervous activities that are responsible for pain sensitivity. The inhibition of noradrenalin-reuptake increases the concentration of noradrenalin in the central nervous system which also leads to an analgesic effect.

Yet another receptor target is called the vanilloid receptor (VR1). VR1 is a non-selective cation channel expressed on the peripheral and central terminals of some types of neurons. It is thought to be a key integrator of pain signals in the nervous system. Of especial interest is the so-called transient receptor potential vanilloid sub-family 1, or TRPV1. Molecules that block or desensitise TRP receptors are considered to have potential regarding the treatment for various pain conditions. They are currently in clinical Phase 2 development.

FIGURE 2: Nerve and spinal cord connections involved in the response to a painful stimulus such as a pin-prick. The sensory nerve enters the dorsal root and passes its messages via interneurons to the motor neurons that leave through the ventral root to produce a reflex muscle response

The longer-term future Top

There is much research devoted to pain relief and the complex mechanisms of pain perception are becoming better understood. With the parallel search both for more effective pain control and a reduction in side-effects, the prospects for medical control of chronic pain especially should be significantly improved within a few years.

By molecular cloning and the use of specialised pain models, several research groups have identified specific ion channels, receptors and neurotransmitters that may be involved in pain. On the basis of such studies, it has been shown that a family of sodium channels is specific to neurons and central pain regulation. Other research targets are calcium ion channels which may be of interest to treat neuropathic pain. The cloning of neurotransmitter receptors has already opened new avenues.

Also, research is targeting bradykinin (a peptide that can significantly enlarge small blood vessels), as it is considered to be involved in peripheral tissues where it augments pain caused by tissue damage and inflammation. Another naturally occurring protein, artemin, could represent an effective new approach to treating neuropathic pain, as its receptor is only found on sensory neurones.

Other research groups are studying the effects of prostatic acid phosphatase (PAP). In preclinical studies, they have shown that the injection of the compound into animals results in a reduction of pain sensitivity that remains significant for three days. Furthermore, the reduction in pain sensitivity is similar to that seen with a dose of 50 microgrammes of morphine, but the morphine analgesia lasts only for five hours.

Another long-term approach to pain control may be through the use of monoclonal antibodies which can be designed to bind with great selectivity to ion channels, membrane receptors or neurotransmitters. One example is an antibody targeting nerve growth factor (NGF) which is being explored in clinical trials with patients suffering from severe pain.