Chronic pain is a highly unmet medical need, and a significant number of patients are not effectively treated with currently available therapies, particularly in chronic debilitating conditions such as neuropathic pain. Neuropathic pain, defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system, is very common for cancer patients, and difficult to manage. It has detrimental impact on the overall quality of life, it impairs the patient's ability to perform daily functions as well as the ability to cope with the disease, further adding to the anxiety, worry and stress of the patient and their family.¹

Doctors and researchers have long sought to make assessments of pain more accurate and independent from numerical rating scales (NRS) or other kind of scales (a review of pain intensity scales can be found here: http://painconsortium.nih.gov/pain_scales/index.html). The lack of objective measurements for pain is also an issue for the design of clinical trials aimed at measuring the extent of pain, as highlighted by the problem of fluctuating baselines for pain (different people have different baselines or pain thresholds, and the baseline for the same person may change), which has been analysed by Elie Dolgin in her piece recently published in Nature Medicine.²

Neuropathic pain and the need to design good clinical trials able to tackle it was also a topic at ESMO, Milan, Oct 8-12, 2010. The opioid use in cancer patients was the focus of an industry satellite symposium on Friday, October 8th August. Caraceni (Fondazione IRCCS Istituto Nazionale Tumori, Milano) opened the session by discussing the opiod availability and use in cancer patients in Europe. Stein Kaasa (Trondheim University Hospital, Norway) and Gail Austin Cooney (Nova Souteastern College of Medicine) focused instead on the side effects of opiod treatment and how to manage them.

Also at ESMO, Marina Garassino (Fatebenefratelli Hospital, Milan), presented the results of a randomised phase II trial for the treatment of neuropathic pain in cancer patients. The trial (NCT00637975) aimed at evaluating the activity and toxicity of fixed dose of the opiod oxycodone versus the anticonvulsant pregabalin. The rationale of the study was the following: evidence suggests that among opioids, oxycodone may have a superior activity compared to the others, and pregabalin, has a proven benefit on the neuropathic component, however, data on their rational combination of the two are lacking. In the NCT00637975 study, 74 patients were randomised to receive either fixed dose of oxycodone at the dose of 10 mg daily and increasing dose of pregabalin (arm A) or fixed dose of pregabalin at the dose of 50 mg daily and increasing dose of oxycodone (arm B). Primary endpoint of the trial was described as a reduction of at least one third of pain with a NRS from 0 to 10, where 0 is no pain and 10 is the most severe pain. The results of the trials were promising (the achievement of reduction of one third of the basal pain was reached in 78.9% and 71.4% of patients in group A and B respectively) and warrant now a confirmation with a multicenter randomised phase III study, as Garassino pointed out.

But not all patients with neuropathic pain are responsive to opiod treatment, as shown for example in a recent survey that was conducted in 2006 in 15 countries in Europe and included Israel. Thirty-four percent of respondents had severe pain (NRS > 8/10, where 0 = no pain and 10 = worst pain). One-third of chronic pain sufferers were not receiving any treatment, whereas a majority used non-medication treatments (i.e., acupuncture, massage, physical therapy) and over-the-counter drugs (e.g., NSAIDS). Only a small percentage of patients used strong opioids, and 40% of the patients reported inadequate control of their pain.³ Therefore within this context it is important to mention also non opiod drugs for neuropathic pain.

Sativex, an oromucosal spray drug based on tetrahydrocannabinol (THC) and cannabidiol (CBD) was developed by the UK company GW Pharmaceuticals, and in June 2010 was approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in UK as a prescription only medicine for the treatment of neuropathic pain in multiple sclerosis.⁴ Sativex is also being prescribed to alleviate cancer pain in the UK and has been marketed in Canada since 2005, while it is available in a number of countries as an unlicensed medicine. The first large scale US Phase IIb trial, Spray Trial (NCT00674609), for cancer patients, reported in March 2010, and a Phase III trial for cancer patients with neuropathic pain is currently recruiting (NCT00872144). To note, Sativex is not marketed in Italy but can be imported through the procedure D.M. 11-2-1997 (ministerial decree on the import of abroad-registered medicinals).5

References

1. Lema MJ, Foley KM, Hausheer FH (2010) Types and epidemiology of cancer-related neuropathic pain: the intersection of cancer pain and neuropathic pain Oncologist 15 Suppl 2:3-8

2. Dolgin E Fluctuating baseline pain implicated in failure of clinical trials Nat Med 16(10):1053

3. Breivik H, Collett B, Ventafridda V et al Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment S. Eur J Pain 10(4):287-333

4. Kmietowicz Z (2010) Cannabis based drug is licensed for spasticity in patients with MS BMJ 340:c3363 

5. DM 11-2-1997: Italy, decree on import of abroad-registered medicinals. The text of the law can be downloaded here: www.ass5.sanita.fvg.it/.../Farmaci%20Estero%20DM%2011%2002%201997.pdf (accessed October 15, 2010).

Additional reading

A Study of Sativex® for Pain Relief in Patients With Advanced Malignancy (SPRAY)  http://clinicaltrials.gov/ct2/show/NCT00674609  

Oxycodone and Pregabalin for the Treatment of Oncological Neuropathic Pain http://clinicaltrials.gov/ct2/show/NCT00637975  

Sativex for Treatment of Chemotherapy Induced Neuropathic Pain  http://clinicaltrials.gov/ct2/show/NCT00872144