PAIN

What is pain?

Acute pain is a defence mechanism - a warning from the body that something is 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 pain), from traumatic or disease-related damage, or from the nervous system itself (neuropathic pain), for example, in diseases such as diabetes or following shingles (post-herpetic neuralgia).

Who does pain affect and what does it cost?

Pain is a very common experience. Despite this, there are few reliable statistics about its impact and economic costs. A survey in 2003 of over 46,000 people in 16 European countries found that about one in five adults had experienced moderate to severe pain several times a week for at least six months (chronic pain). About one-third of those reporting chronic pain said that they were constantly in pain.

A UK survey found that the most common cause of pain was back pain (27 per cent), followed by arthritis (24 per cent), headache (16 per cent) and injuries (8 per cent). A separate survey conducted in three UK cities found that overall about 8 per cent of respondents had chronic neuropathic pain.

The British Pain Society has reported that back pain alone is estimated to cost the exchequer about £5 billion per year in direct and indirect costs, but the total cost of treating all forms of chronic pain is not known.

Present treatments and shortcomings

Management of chronic pain seeks to eliminate pain completely, while using the minimum amount of medication that prevents it recurring. Therapy often needs to be individualised, but generally follows the three-step 'pain ladder' established by the World Health Organisation in 1990.

1. Non-opioid analgesics (painkillers) such as paracetamol, or aspirin, or non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, diclofenac, naproxen or selective cyclooxygenase-2 (COX-2) inhibitors are used first for treating musculoskeletal pain. (See Osteoarthritis and Rheumatoid Arthritis)
2. If this proves inadequate, a weak opioid such as codeine, dihydrocodeine or tramadol is added or substituted. In addition, steroids, local anaesthetics, anti-emetics or tranquillisers may be given to increase the effectiveness of these analgesics.
3. In severe, intractable pain, strong opioids such as morphine, oxycodone, hydromorphone, fentanyl and methadone are used. These include skin patches of fentanyl (Durogesic, Janssen-Cilag) and slow-release morphine, which give a more even and prolonged effect than injected or oral treatments. Opioids are often required for treating cancer-related pain.

Other medicines are available for treating types of neuropathic pain, such as trigeminal neuralgia and diabetic neuropathy. These include carbamazepine (Tegretol, Novartis), gabapentin (Neurontin, Pfizer), duloxetine (Cymbalta, Lilly) and pregabalin (Lyrica, Pfizer).

None of the existing analgesics (painkillers) is ideal. Strong opioids are addictive and can cause constipation. In severe pain, the doses required have a marked sedating action and affect respiration. Weak opioids such as codeine are only able to control mild to moderate pain. Non-opioid medicines such as aspirin and NSAIDs are only suitable for mild pain and may cause gastroduodenal ulcers. Many people have chronic pain that is difficult to control, or experience pain as the effect of their medicine wears off, and the need for better alternatives is clear.

What's in the development pipeline?

The sensation of pain is complex (Figure 2) and this gives considerable scope for developing medicines that act in new ways, or on different parts of the nervous system.

For example, GW Pharmaceuticals has several projects in progress to develop pain-relieving medicines based on cannabinoids that act on receptors in the nervous system. Delivered as a spray, one (Sativex) is being tested in cancer pain and in pain due to spinal cord injury (both in phase 3 trials), while another is in Phase 2 trial in post-operative pain. A fourth is in Phase 2 trial for pain originating in the nervous system. Others have also targeted cannabinoid receptors, with compounds from Novartis (SAD 448) and GlaxoSmithKline’s GSK 842166 in Phase 1 and PRS-211,375 (Cannabinor, Pharmos) in Phase 2 trial.

Other compounds in Phase 2 trials that act in new ways include the calcium-channel blocker MK-6721 and the vanillin receptor-1 antagonist MK-2295, both being developed by Merck Sharp & Dohme, F-13640 from Pierre Fabre, Pfizer's monoclonal antibody PF-4383119 and the bradykinin antagonists Icatibant and SSR 240612 from sanofi-aventis. Several companies also have compounds at this stage that act on opioid receptors, including Penwest (PW 4142), Vernalis (buprenorphine nasal spray, for post-operative pain) and Wyeth (methylnaltrexone - an opioid receptor antagonist that may reverse the action of opioids that cause constipation).

Neuropathic pain remains particularly difficult to treat, and there are a large number of new compounds undergoing clinical trials. Wyeth's desvenlafaxine is in Phase 3 study, as are Schwarz Pharma's lacosamide and Avanir's AVP 923, a combination of dextromethorphan and quinidine under study in diabetic neuropathy. Also at Phase 3 is NGX-4010, from Neurogesx, that is being developed for use in post-herpetic neuralgia.

Of the Phase 2 compounds for neuropathic pain, several act on nerve pathways involving the neurotransmitter glutamate. These include CNS-5161 from CeNeS Pharmaceuticals, and memantine and neramexane from Forest Labs, as well as Vernalis's V3381, in trial for diabetic neuropathic pain. Other compounds at this stage that act in new ways are Newron's ralfinamide, Takeda's TAK-583, and GSK’s p38 kinase inhibitor GSK 681323.

One new compound which works in a different way comes from an unexpected source: the marine cone shell. One cone-shell toxin, ziconotide (Prialt, Eisai) is already available, and this works as a calcium-channel blocker. The new compound (ACV1, Metabolic Pharmaceuticals) has been shown instead to act by blocking a subclass of receptors in the nervous system.

FOR FURTHER INFORMATION CONTACT:

ACTION ON PAIN
20 Necton Road
Little Dunham
Norfolk, PE32 2DN
Phone: 0845 603 1593 (Helpline)
Website: www.action-on-pain.co.uk

BACKCARE
16 Elmtreee Road
Teddington
Middlesex, TW11 8ST
Phone: 020 8977 5474
Website: www.backcare.org.uk