A Phase II Study to Establish the Efficacy and Toxicity of Sodium Valproate in Patients With Cancer-Related Neuropathic Pain

Transcription

1 204 Journal of Pain and Symptom Management Vol. 21 No. 3 March 2001 Original Article A Phase II Study to Establish the Efficacy and Toxicity of Sodium Valproate in Patients With Cancer-Related Neuropathic Pain Janet R. Hardy, MD, BSc, MB ChB, FRACP, Elizabeth A. J. Rees, BSc (Hons), RGN, Bridget Gwilliam, BSc, RGN, Julie Ling, BSc (Hons), RGN, Karen Broadley, MBBS, MRCP, and Roger A Hern, MSc Department of Palliative Medicine (J.R.H., E.A.J.R., B.G., K.B.) and Department of Statistics (R.A.), The Royal Marsden NHS Trust, London and Surrey, United Kingdom, and Department of Palliative Care (J.L.), St. Lukes Hospital, Dublin, Ireland Abstract The efficacy and toxicity of sodium valproate for cancer-related neuropathic pain was evaluated in a phase II study at this cancer center. Twenty-five patients entered the study over a 13 month period. Pain was assessed using a pain scale based on the Brief Pain Inventory at days 0, 8 and 15. Nineteen patients completed the two week study period, one patient discontinued treatment because of toxicity, and five discontinued because of progressive disease. The most frequently observed side effects were drowsiness, unsteadiness, nausea, and decreased appetite. Response was defined as a decrease in pain score in the absence of increased need for analgesic medication. The response rate for average pain at day 15 in assessable patients was 55.6% ( %, 95% CI), but response rates varied considerably depending on the mode of analysis. Baseline efficacy data have been gained on which to base future comparative studies against antidepressants. J Pain Symptom Manage 2001;21: U.S. Cancer Pain Relief Committee, Key Words neuropathic pain, cancer, anti-convulsant, sodium valproate Introduction The role of antidepressants in the treatment of nonmalignant neuropathic pain is wellestablished. 1 The benefit in cancer-related neuropathic pain has been shown in a few randomized studies and several uncontrolled series, 2 in which response rates range from %. Anticonvulsants are also widely used in this Address reprint requests to: Janet Hardy, MD, Department of Palliative Medicine, The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom. Accepted for publication: April 18, condition, but there is little evidence to support their use. Although the effectiveness of anticonvulsants in chronic pain syndromes has been shown in a systematic review, 3 only one randomized study in cancer pain was identified. 4 Moreover, there are considerable differences in everyday practice, for example, in choosing the best anticonvulsant, for how long, and at what cost with respect to side effects. Sodium valproate is the anticonvulsant used most commonly in this center for the treatment of neuropathic pain, as it is thought to be effective and to have fewer side effects than carbamazepine. It is recognized that there is a need for randomized comparative studies of U.S. Cancer Pain Relief Committee, /01/$ see front matter Published by Elsevier, New York, New York PII S (00)

2 Vol. 21 No. 3 March 2001 Sodium Valproate for Cancer-Related Neuropathic Pain 205 anticonvulsants against antidepressants or even placebo, but historically these have been difficult to perform in the palliative care population. Moreover, the true efficacy of these drugs in cancer-related neuropathic pain is unknown. We, therefore, elected to undertake an open phase II study of sodium valproate in cancer- related neuropathic pain in an attempt to assess the relative effectiveness and side effects of the drug in this patient group and to identify levels of activity that would warrant a large comparative phase III study. Methods This study was made for an open label phase II study of sodium valproate for the treatment of cancer-related neuropathic pain. Cancerrelated neuropathic pain was defined as any predominately dysesthetic, hyperesthetic, aching, shooting or lancinating pain corresponding to an area of nerve damage directly attributable to malignant infiltration, compression or inflammation. All patients referred to the Department of Palliative Medicine with cancer-related neuropathic pain were eligible for entry if they were 18 years of age or older; had been receiving opioids for at least 48 hours; were thought capable of completing the study and signing a written informed consent; and had not had radiotherapy, or a nerve block or other anesthetic procedure to the presumed site of nerve damage within 2 weeks of the study. Patients receiving antidepressants or corticosteroids were included, provided these had not been started or increased in the 7 days prior to entry. Patients receiving chemotherapy or hormone therapy were included if in the opinion of the investigator this was unlikely to cause the pain. Those patients already receiving anticonvulsants were excluded, as were those with known renal or hepatic impairment that would preclude the use of sodium valproate in normal clinical practice. All patients were commenced on sodium valproate at a dose of 200mg twice daily (bd). If the pain was not controlled and there was no evidence of toxicity, the dose was escalated by 200mg bd every 2 3 days to a maximum of 600mg bd. Once the patient was pain-free, there was no further dose escalation. Dose increases were made at the physicians discretion, taking into account the general clinical situation, pain response, the age of the patient and any toxicity noted. Patients were encouraged to take their normal opioid and co-analgesics concurrently. Analgesic use and dosages were recorded at days 0, 8 and 15. Patients were formally assessed on days 0, 8 and 15. Baseline demographic data plus a careful description of the pain was noted at baseline (day 0). On each subsequent occasion, WHO performance status, concomitant medication and any adverse events were noted. A doctors assessment at each visit recorded whether there had been any subjective improvement in overall pain. Pain was assessed using a linear rating scale based on the Brief Pain Inventory (BPI)-short form, 5 modified for the assessment of nerve pain. 6 Patients were required to score different aspects of their pain (i.e., average pain, least pain, pain right now, and worst pain in the previous 24 hours ) on a numerical 10 point scale ranging from 1 ( no pain ) to 10 ( pain as bad as you can imagine ). They were also asked to score percentage pain relief (0 100%) and how the pain was affecting their every day activity on numerical activity scales ranging from 1 ( pain does not interfere ) to 10 ( pain completely interferes ). Patients were asked to complete the questionnaire on a daily basis but only those of the study days 0, 8 and 15 were used for the analysis. Response was analyzed in 3 ways: a) response by pain category: pain scores were grouped into four categories: 1 no pain, 2 to 4 mild pain, 5 to 7 moderate and 8 to 10 severe pain. Responding patients were defined as those with a reduction in average pain score by one or more category e.g., moderate to mild. 7 b) response by absolute pain score: responding patients were defined as those with any reduction in numerical score for average pain e.g., 7 to 6 or 7 to 4. c) response by 50%: responding patients were those who had shown a 50% decrease in average pain score e.g., 8 to 4 or 6 to 3. Pain relief was documented as positive if there was any increase in percentage pain relief calculated as a reduction in pain relief deficit using response by absolute score and 50%, as described above.

3 206 Hardy et al. Vol. 21 No. 3 March 2001 The effect of pain on daily activity was analyzed by the assessment of the absolute score for each individual activity, as well as by a total activity score and comparing the scores at days 0, 8 and 15. Only absolute scores were used in this analysis. Any decrease in score was considered to be a response. Non-responding patients were defined as those with an increase, or no decrease, in pain score, those requiring a 30% increase in their concomitant opioid dose, and/or those requiring an alternative neuropathic agent to control nerve pain despite maximum dose of sodium valproate. Patients were asked specifically about indigestion, change in appetite, drowsiness, nausea, unsteadiness of gait and any other symptoms that had developed at each study visit. These side effects were scored on a 1 to 4 scale corresponding to not at all to very much and were assessed on days 8 and 15. Patients were scored as positive for a side effect if their score at day 8 or 15 was worse than that at baseline (day 0). This study employed a Gehan two-stage phase II design, the aim being to estimate the pain response rate with a standard error of 10% with a minimum level of acceptable pain relief set at 20%. It was planned to enter 14 patients in the first stage with a further 0, 1, 6, 9 or 11 patients to be entered in the case of 0, 1, 2, 3 or 4 responses, respectively, in the first 14 patients. Results Twenty-five patients with advanced malignant disease were entered into the study from November 1996 to May Patient characteristics are shown in Table 1. The median survival of patients who entered the study was just under 6 months (170 days, range days) from date of study entry. Nine patients were still alive at the time of analysis. The majority of patients (22) had a WHO performance status of 1 or 2 at the start of study. All patients were receiving opioids, 2 patients were receiving antidepressants and six were taking corticosteroids concurrently. The neuropathic pain was classed as primarily dysesthetic in 4 patients, lancinating in 10 and mixed in 11. Nineteen patients completed the two-week treatment period. Six patients were withdrawn from study; one because of side effects (shaking), one because of uncontrolled pain, and four because of other adverse events which in the opinion of the investigators were thought most likely to be due to disease progression and not to be related to the study medication. Seventeen patients (89%) continued on sodium valproate following completion of the study, as it was thought by either patient or doctor to be of benefit. Response was analyzed in those patients completing the day 8 and day 15 pain assessments. The results according to each of the 3 methods of analysis (response by pain category, by absolute pain score and by 50% improvement in pain score) are shown in Table 2. Response with respect to interference with daily activities is shown in Table 3. There was poor agreement between improvement in average pain and improvement in pain relief (58%) and between improvement in average pain and improvement in activity (44%). Similarly, in only 38 % at day 8 and 56% of cases at day 15 did the doctors subjective assessment of pain correspond to the patients objective assessment in the pain scores. The median dose of sodium valproate at day 8 was 400mg bd (range mg, n 23); the median dose at day 15 was 600 mg bd (range mg, n 19). Of those patients who had a response (as defined as a reduction in average pain category), 1 patient was on 200mg bd, 2 were on 400mg bd and 7 were taking 600 mg bd. The median dose for those patients continuing on sodium valproate following completion of the study was 600mg bd. Table 4 shows the number of patients who recorded a worse toxicity score at either day 8 or 15 as compared to baseline. The most common side effects were drowsiness, unsteadiness and decreased appetite. It was often difficult to differentiate true toxicity (definitely attributable to study drug) from symptoms related to progressive disease. Only one patient discontinued treatment because of side effects thought directly attributable to the study drug (i.e., uncontrolled tremor) that improved following cessation of the drug. This patient was withdrawn prior to day 8 and is therefore not included in the formal toxicity assessment. Twenty-one of 23 evaluable patients had no change in analgesia and two patients had increased analgesic requirements over the two

4 Vol. 21 No. 3 March 2001 Sodium Valproate for Cancer-Related Neuropathic Pain 207 Sex: Age: Table 1 Patient Characteristics (n 25) Cancer Diagnosis: Breast 12 Lung 7 Cervix 2 Prostate 2 Other 2 WHO performance status: female, 9 male median 62 years (range years) carcinoma week study period. In no patient was there a decrease in pre-treatment opioid requirement whilst on sodium valproate. Discussion Sodium valproate is licensed for the control of all forms of epilepsy. The mechanism of action is unknown but may involve an interaction with GABA metabolism in the brain. It has been postulated that a membrane stabilizing effect inhibiting paroxysmal discharges may be important with respect to its activity in neuropathic pain. The most common side effects of sodium valproate are gastrointestinal: anorexia, nausea and vomiting. Effects on the central nervous system include sedation, ataxia and tremor. Although anticonvulsant drugs have been used in the management of chronic pain for many years, only carbamazepine and phenytoin are licensed for this indication, and then only for the treatment of trigeminal neuralgia. Both carbamazepine and sodium valproate are used commonly in cancer patients for the management of neuropathic pain but the evidence to support their use is purely anecdotal. Historically, they have been recommended for neuropathic pain of a shooting or lancinating nature. Analgesic effects are seen at doses below an effective anticonvulsant dose, can take up to 5 days to become apparent, and can be dose-related. A systematic review of anticonvulsants in the management of nonmalignant pain showed evidence of effectiveness in trigeminal neuralgia and diabetic neuropathy, and for migraine prophylaxis. Minor adverse events occurred almost as often as benefit. 3 One randomized comparison of an antidepressant with an anticonvulsant in non-cancer pain showed the former to be more effective with fewer side effects. 8 The purpose of this study was to formally document the effectiveness and side effects of sodium valproate in cancer-related neuropathic pain prior to embarking on a larger randomized study against antidepressants. The response rates documented here vary considerably according to the method of analysis and the particular aspect of pain being considered. They range from 67% for worst pain when looking at a reduction in pain category, to 22% for a 50% reduction in least pain score (Table 2). The confidence intervals are all very Pain Table 2 Patient Response Evaluation Completed Day 8 % Response Completed Day 15 % Response a) Reduction in pain category Average ( ) ( ) Worst ( ) ( ) Least ( ) ( ) b) Reduction in absolute score Average ( ) ( ) Worst ( ) ( ) Least ( ) ( ) Pain relief a ( ) ( ) c) 50% reduction in pain score Average ( ) ( ) Worst ( ) ( ) Least ( ) ( ) Relief a ( ) ( ) a refers to reduction in pain relief deficit

5 208 Hardy et al. Vol. 21 No. 3 March 2001 Table 3 Interference with Daily Activities: Reduction in Absolute Score Completed Day 8 % Response completed Day 15 % Response General activity ( ) ( ) Mood ( ) ( ) Walking ( ) ( ) Work ( ) ( ) Relationships ( ) ( ) Sleep ( ) ( ) Enjoyment ( ) ( ) Total activity ( ) ( ) wide, reflecting the small numbers. As would be anticipated, the results are generally better when one considers a reduction in absolute score, which is much easier to achieve than a 50% reduction in pain score. Pain relief, as reflected by a reduction in interference with daily activities, was generally less than 30%. The least effect was seen with sleep, while walking and relationships tended to show the greatest improvement. All response rates were lower when all patients originally entered are considered on an intention-to-treat basis. This study illustrates the importance of documenting the method of analysis when reporting the results of pain relief studies and suggests that standardization of method is essential if pain studies are ever to be compared. Of concern was the marked discrepancy between the doctor s subjective assessment of pain and that recorded by the patient on the pain scales. There was consistency in pain assessment (better or worse) in only 38% of cases at day 8 and in 56% at day 15. Eighty-nine percent of patients continued on sodium valproate following completion of the study period, as it was thought by either the patient or the doctor to be of benefit even though the objective response rates by any of the means of analysis are much lower than this. This finding also supports the need for larger comparative trials of anticonvulsants to gain an evidence base for the use of these potentially harmful drugs. In a review of placebo-controlled trials of antidepressants in neuropathic pain, the placebo response was often much higher than the usually expected 30 %, 9, 10 suggesting that the placebo response in this study might also have been be considerable. We may be criticized for the relatively low doses used. Doses up to 2.5gm/day have been used for the control of neuropathic pain. It was the opinion of the physicians in the trial consultation group that responses are seen at low doses. If no response has been seen at 600mg bd there is unlikely to be a response at higher doses and any worthwhile response is likely to be seen within 2 weeks. This study has all the shortcomings inherent in an uncontrolled, nonrandomized trial and illustrates some of the difficulties inherent in conducting studies in palliative care. Even though the inclusion and exclusion criteria were kept as wide as possible to correspond to every day clinical practice, it took 13 months to accrue 25 patients. The patients in this study were relatively fit, with a median performance status of 1 at the start of the study, and the study period was short (2 weeks). Even so, the attrition rate was high. Despite these difficulties, we have shown that sodium valproate does have activity in cancerrelated neuropathic pain and has given a base- Table 4 Toxicity Assessments Compared to Baseline Completed Worse at Day 8 Completed Worse at Day 15 Indigestion Appetite Drowsiness Nausea Unsteadiness

6 Vol. 21 No. 3 March 2001 Sodium Valproate for Cancer-Related Neuropathic Pain 209 line from which to proceed to a comparative phase III study against an antidepressant. Such a study will necessitate large numbers of patients, however, and will always be difficult within a palliative care population. It is unlikely that this could ever be done outside a large multicenter trial. The frequency with which side effects are reported for both groups of drugs makes it essential that some evidence base is established to justify their frequent use. Acknowledgments The authors would like to thank Sanofi Winthrop for supplying the medication for this study and for the contributions made from the South Thames Palliative Care Research Group in the design and evaluation of this study. References 1. McQuay HJ, Tramer M, Nye BA, et al. A systematic review of antidepressants in neuropathic pain. Pain 1996;68: Breitbart W. Psychotropic adjuvant analgesics for cancer pain. Psycho-Oncology.1992; 1: McQuay HJ, Carroll D, Jadad AR, Wiffen PJ, Moore RA. Anticonvulsant drugs for management of pain: a systematic review. BMJ. 1995; 311: Yajnik S, Singh GP, Singh G, Kumar M. Phenytoin as a coanalgesic in cancer pain. J Pain Symptom Manage 1992; 7,4: Daut RL, Cleeland CS, Flanery RC. Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain 1983; 17: Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: The neuropathic pain scale. Neurology 1997;48: Schug S, Zech D, Dorr U. Cancer pain management according to WHO analgesic guidelines. J Pain Symptom Manage 1990;1: Leijon G, Boivie J. Central post-stroke pain a controlled trial of amitriptyline and carbamazepine. Pain 1989;36: Hardy JH. Placebo-controlled trials in palliative care: the argument for. Palliative Medicine. 1997;11: McQuay H, Moore RA, Eccleston C, Morley S, Williams AC. Systematic review of out- patient services for chronic pain control. Health Technology Assessment 1997;1 6.