Record of Proceedings: December 2, 2004 - Scientific Advisory Panel on Neuropathic Pain (SAP-NP)

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Scientific Advisory Panel on Neuropathic Pain

Record Of Proceedings

Teleconference
December 2, 2004

Panel Members Present: Dr. William Pryse-Phillips, (Chair), Dr. John Clark, Dr. Vera Bril

Health Canada (HC) Working Group Members:
M. Davis (SAP Secretariat Officer, PB), S. Mithani (BCANS), E. Ormsby (SAP Scientific Advisor, PB), C. Petersen (BCANS), C. Strnad (Scientific Advisor, PB)

Abbreviations for Health Canada Directorates & Bureaux and other terms used in this record:

BCANS = Bureau of Cardiology, Allergy and Neurological Sciences
CNS = Central Nervous System
DNP = Diabetic Neuropathic Pain
GP = General Practitioner
HC = Health Canada
MS = Multiple Sclerosis
NSAIDS = Non-Steroidal Anti-Inflammatory Drugs
PB = Policy Bureau
PHN = Post-herpetic Neuropathy
PNP = Peripheral Neuropathic Pain
SAP-NP = Scientific Advisory Panel - Neuropathic Pain
SF36 = Short Form 36
TPD = Therapeutic Products Directorate
VAS = Visual Analogue Scale

• Roll Call, Review Agenda, Conflict of Interest (COI) Declarations - S. Mithani
  
  The meeting was called to order by the Director of the Bureau of Cardiology, Allergy and Neurological Sciences (BCANS) who welcomed and thanked the expert members for agreeing to take part in this teleconference.
  
  The members self introduced and verbally confirmed that their Conflict of Information status had not changed since they submitted their written declarations upon being contacted for participation in this panel.
  
  
• Review of process for teleconference - E. Ormsby / S. Mithani
  
  The members were thanked for volunteering and were given an explanation of how the record of proceedings is to be prepared. There will be no attribution for the advice given. Health Canada (HC) will monitor the discussions and will only take part during the discussion if clarification is necessary or if the panel members need more information.
  
  After approval by the Chair and panel members, the record will be posted on HC's web site.
  
  
• Deliberation of questions & finalization of recommendations -
  W. Pryse-Phillips
  
  A series of questions was sent to the three members of the SAP-NP prior to the teleconference for their review. The discussion during the teleconference centred around these questions, but was not always solely specific to each question, and did not necessarily take place in the order the questions were posed. This record presents the questions as posed (in italics), followed by a summary of the discussions for each group of questions (regular font.)

Neuropathic Pain Questions

1. General:
   
   
   1. What are the primary issues regarding diagnosis and pharmacological treatment of neuropathic pain?
      
      
   2. Which issues are generalizable irrespective of neuropathic pain etiology, i.e., post-herpatic neuropathic pain (PHN) versus diabetic neuropathic pain (DNP), central versus peripheral neuropathic pain (PNP)? Which issues are specific to neuropathic pain?
      
      The clinical presentation of diabetic and post-herpetic pain are fairly clear with characteristic symptoms and history, and can be readily diagnosed.
      
      The patho-physiology of neuropathic pain is not well understood. There are a number of abnormal processes occurring within the nervous system as a result of damage to the peripheral or CNS, including the problem of plasticity/neuronal reconfiguration. Pain associated with this disorder may be a result of either large or small fibre injury; there is speculation that the latter is associated with inflammatory pain. Direct nerve injury is associated with sharp shooting pain; diabetes/herpes are often associated with burning pain . There is generally not enough attention paid to this aspect of neuropathic pain, and whether specific treatments may work better for specific patho-physiologies.
      
      With respect to pharmacological treatment of neuropathic pain, treatment can be difficult since most of the interventions used have side effects and may not work (for example, only two thirds of patients in controlled clinical trials typically respond, and those patients may only respond by a third). There are major concerns in the treatment of patients with neuropathic pain because good treatment algorithms for treating a broad spectrum of neuropathic pains do not exist. Furthermore, current treatment guidelines are not written in terms of underlying patho-physiology, but rather by disease history (diabetes, herpes). It is difficult to predict whether a patient will respond, and consequently, many agents need to be tried before a patient can be managed appropriately.
      
      
2. Treatment of neuropathic pain:
   
   
   1. Standard of care in Canada , first line, monotherapy, adjunctive therapy, polytherapy?
      
      
   2. How does a clinician approach the treatment of specific types of neuropathic pain, central versus peripheral, multiple sclerosis (MS) versus spinal cord injury?
      
      
   3. Are the standards similar or the same for USA and Europe ? What are some of the more significant differences, if any?
      
      
   4. Are there any specific drugs that are not used (or used with extreme caution) due to safety concerns?
      
      
   5. What types of neuropathic pain (eg, tingling, shooting, electrical, etc.) are considered more resistant to treatment?
      
      
   6. Does pain severity at baseline correlate with treatment response? In other words, which group of patients (with moderate or severe pain intensity) would be expected to respond better (highest pain relief) to current medications?
      
      
   7. Is concomitant use of multiple medications for pain relief a standard practice in clinical management of DNP?
      
      Although there are different national standards of care in other countries, generally, the standard of care in Canada is similar to that of the US/EU. There may however, be differences in the availability of treatments between countries. In Canada , tricyclics may be more commonly used than gabapentin for example, because they are cheaper and are covered by the provincial drug benefit plans (reimbursement issues). Treatment trends and the use of particular agents may be different across Canada due to provincial differences in drug availability and regulations of drug benefit plans. (For example, gabapentin is available in Quebec for this indication under the provincial plan, but not in Ontario ; therefore, tricyclics tend to be used in Ontario .)
      
      References were made to two articles in the literature:
      
      
      • 1. Clinical Journal of Pain; Volume 5, # 3 (April 2004) Clinical Characteristics and Economic Costs of Patients with Painful Neuropathic Disorders.
        
        
      This article reviews the approaches used for the treatment of neuropathic disorders; these are similar to the approaches used in Canada .
      
      
      • 2. Review article by Kingbury (1997) on Controlled Clinical Trials of Peripheral Neuropathic Pain and Complex Regional Pain Syndromes.
      
      In this article, the peripheral neuropathic pain approach mentioned appears to be an accepted international standard, depending on the availability of the drugs. The Cochrane reviews on peripheral neuropathic pain also support the above as a standard, as well as noting that although efficacy is present, it is limited (i.e., efficacy results in small numbers of patients have been somewhat modest).
      
      Currently, treatment is based on etiology rather than patho-physiology of neuropathic pain. There is a need to study what etiologies or patho-physiologies lead to which treatment options. In this patient population, there is often a blend of several types of pain, and the pain changes with time (fluctuating, multi-categorical). The agents currently being used have non-specific effects on the pain. Consequently, it is difficult to delineate the patho-physiology of the pain.
      
      Initially, patients are treated with monotherapy because of difficulties in precise diagnosis and the understanding of underlying etiological processes; most patients are treated with the simplest agents first and then get switched based on knowledge of different patho-physiologies of pain. Monotherapies can be tried in sequence, and when that fails or is of limited benefit, polytherapy is used for patients who remain highly distressed from pain. They are treated with what they can tolerate to relieve pain. It is important to note that patients with diabetic neuropathy may find it hard to tolerate multiple medications due to potential for worsening of underlying conditions such as ataxia. Other treatment options such as massage therapy, acupuncture, laser therapy, TENS, stimulators, etc., may also be used. A substantial proportion of patients (probably the majority) will require polytherapy. Actual percentages may be dependent on whether primary vs. secondary vs. tertiary care centres are sampled.
      
      Although there is a tendency to use the same medications across all pain states, this is not based on data, and in fact no single medication is effective across all types of pain. When there is a peripheral inflammatory component to the pain, COX-2 inhibitors may be used. Non-steroidal anti-inflammatory drugs should be avoided in diabetic neuropathy patients due to renal toxicity. Since neuropathic pain has a temporal as well as pathological gradient, what may work early in a condition may not work later, based on changes in the nervous system related to the underlying condition, e.g. NSAIDS are ineffective for PHN once the inflammatory component has settled.
      
      It was suggested by the panel that initial patient management should be done by a specialist/expert in this field (note: this could be a family physician with enhanced knowledge) to ensure that the right drugs/doses/interventions are being used in the management of these conditions.
      
      
3. Consensus on the measurement of neuropathic pain:
   
   
   1. What is/are the clinical instruments/scales used to measure neuropathic pain, central or peripheral?
      
      
   2. According to these scales (above), what is considered clinically meaningful neuropathic pain relief?
      
      
   3. What would be the clinical impact of the level of neuropathic pain relief as shown in the attached table (see Annex 1)?
      
      For assessments made on scales such as the Likert scale or Visual Analogue Scale (VAS), (see data provided in annex 1) anything that shows minus score on these scales demonstrates a pharmacological effect, and would be considered significant. Whether such a change on a VAS scale is clinically significant is perhaps best answered by looking at secondary measures, i.e., how it affects the patient. A conclusion of a clinically meaningful effect should probably be based on more than one scale.
      
      With respect to the VAS scale, level 4 is generally considered to be a dividing line. Above 4 means that pain is affecting the patient's life, which indicates a need for medications; below 4, experience suggests that many patients can "live with it." Patients entering studies typically start at about 6. It is important to note that for a clinically meaningful change, the patient does not have to achieve "below 4"; a change from 6 to 4 would also be considered significant because the patient is moving from a level that is not tolerable to one that is far more tolerable. None of the pharmacological agents currently used removes the pain totally, i.e., patients almost never become "pain -free."
      
      The objective of treatment is to aim to get the pain score to under 4. Previously, a 50% decrease in pain was thought to be the minimum requirement for significance, but a drop from 6 to 4 which is approximately 30% is now also considered significant. It is also important to take into account an individual patient's baseline. In general, a 30% or more change is regarded as clinically important.
      
      In order to conclude that a treatment has been effective in neuropathic pain, there must be relief for a particular symptom, and the secondary measure must go in the same direction. VAS is the current acceptable primary measure which is subjective, but is a direct measure of pain by the patient. In addition, the patient's impression of change is important, i.e., the global patient impression. The panel did not feel that there should be a "co-primary" with the VAS scale, but rather indicated that additional secondary measures are important. Patient global impression should be used as a secondary measure, although, we cannot be sure how much weight to put on it because it can be affected by many variables that are not pain related. For instance, the patient may not feel that "life is better" for many reasons that are unrelated to the actual level of pain-relief. The same may be true of measures of "functioning" or "impairment", in terms of not being necessarily correlated with pain levels. It may also be useful to look at the global satisfaction scale and other information which may provide an overall picture of the usefulness of the treatment.
      
      Some patients who have severe long- term pain find it difficult to tell if their pain is better, and therefore, more than one alternative measure may be needed to determine if there is improvement. Although the primary measure is VAS, it cannot be considered as entirely reliable; a secondary measure to validate the assessment (that pain has improved) may be necessary.
      
      
4. Clinical risk assessment:
   
   For each neuropathic pain population (MS, DNP, PHN, CNS injury), what are the specific safety issues and desired benefits that determine the optimal treatment choice?
   
   
5. Role of psychotropic effects on efficacy:
   
   
   1. What is the role of effects such as sedation, somnolence, anti-depression, dizziness, etc., of treatments commonly used in relieving neuropathic pain? Are they considered to contribute to beneficial effects (efficacy)?
      
      
   2. Except for local anaesthetics, are other treatments considered to have a clinically significant level of psychotropic effects?
      
      
   3. How prevalent is the use of opioids and how effective do they appear to be in clinical practice?
      
      
   4. Prevalence and effectiveness of drugs such as gabapentin, SSRIs and others in the management of neuropathic pain.
      
      

      The context in which somnolence is described is important. For example, does the patient feel sleepy when he/she wakes up? Or does the drug help in getting the patient a good night's sleep? Consequently somnolence can be perceived to be a positive or negative effect. The positive or negative impact of reported somnolence is not always easy to determine. There may be a need to have structured questionnaire to determine whether sedation is a beneficial effect or a side effect. Both the frequency and severity of somnolence need to be captured; 20% to 30% (or more) of patients reporting somnolence is not unusual, but patients may nevertheless may want to stay in the study because of the benefits. Thus, the benefit-risk ratio must be weighed appropriately. If an individual patient feels too much somnolence for their liking, especially if it happens during the day and is significant, they will likely simply refuse to take the drug and drop out of the study. It is also important to note the potential confounding factor which is that the presence of pain is often associated with sleep disturbance, such that somnolence can be a byproduct of lack of pain relief.

Clinical trial issues

1. Efficacy measures:
   
   
   1. What are the:
      
      
      • validated primary and secondary measures for efficacy in central and peripheral neuropathic pain?
        
        
      • internationally accepted assessment tools and the effect sizes expected to have clinical significance/clinical meaning (See Annex 1)?
        
        
   2. What is the definition of a "Responder" in the clinical context of MS, PHN, DPN? For example, could it be 30% level of pain relief, 50%, or another figure?
      
      
   3. Any comments/concerns with respect to dose-response studies? In other words, how long should a patient be treated with a certain dose of a drug before the degree of pain relief can be determined (see "Trial Duration" section below)?
      

      Efficacy measures range from: the neuropathic pain scale, the McGill questionnaire, time to exit, time to remedication, scales like pain ruler, numerical, visual analogue scales, inventories, SF36, profile of mood states, etc. The VAS scale and Likert scale can be used as primary measures of efficacy. Changes in main daily pain scores on these scales averaged over 5 to 7 days allow for comparisons, and have now become a standard primary measure of efficacy. Other scales can be supportive as secondary measures.
      
      Secondary measures include 30% and 50% responders, which may be considered as a meaningful change in pain in a study. A 30% reduction in pain should be considered as a reasonably clinically significant response, but it is also important to look at the percent of patients with a 50% reduction in pain.
      
      With respect to secondary measures, the McGill questionnaire and sleep disturbance scales are also very important, especially in diabetics, where sleep disturbance from pain/underlying conditions is a problem. Therefore a drug that helps patients sleep better is welcome (one of the reasons why tricyclics and anticonvulsants are favoured in this population). Patient's global impression of change (PGI-C) can also be considered a more meaningful assessment than the clinician's global impression of change (CGI-C).
      
      Physical function, emotional function, clinical global impression of success, unwanted effects lists, measure of adherence to the program, and time to re-medication can also be useful as secondary measures. Ideally, secondary measures should change in the same direction as the primary measure, (regardless of what the secondary criteria are), which provides supporting evidence for the efficacy of the drug. Also, any scales that are used in studies should be validated scales.

2. Trial duration:
   1. What is an acceptable duration of treatment required in order to assess efficacy in the short-term?
      
      
   2. Please comment on the usefulness of placebo-controlled vs. active-controlled vs. 3-way studies (an active arm in addition to placebo and study drug arms) in these trials.
      
      
   3. What is an acceptable duration of treatment required in order to assess efficacy in the long-term, i.e., maintenance of initial efficacy?
      
      At least 4 to 8 weeks, although up to 12 weeks may be optimal. In order to ensure that patients are not in terrible discomfort, "time to remedication" should be used as an endpoint. Generally, short term can be considered as 3 to 4 weeks beyond the dose-escalation phase. Beyond this period, studies should be considered long term, depending on the reporting of pain intensity by patients. The examples in annex 1 show dose escalation phases. Therefore, patients should be monitored on drug therapy for 4 to 6 weeks after the end of the trial; a total of 8 to 12 week trials would be sufficient to demonstrate efficacy. If a response to treatment occurs over 8 to 12 weeks, in clinical practice many patients will continue to respond over time.
      
      Open label data reflect our findings that with individual patients, over time, it is possible to maintain a benefit in a reasonable proportion of patients. The clinical reality is that almost no patient is pain-free without continuous therapy of some kind; many patients try "drug holidays" but the pain comes back and drugs are re-started.
      
      One of the panel members was of the opinion that using a placebo group for these indications is appropriate if the patient is informed of the fact that there are other treatments, or if patient has already failed other medications, and there is a rescue medication available within the parameters of the trial. Another panel member commented that there are difficulties with placebo-controlled trials, especially if a patient is removed from an effective medication to enter the trial. This member was concerned with how one would deal with breakthrough pain within the confines of the protocol? In addition, ethics committees have shown reluctance to approving placebo control trials for this indication. There are also issues surrounding the interpretation of "standard of care." Furthermore, if protocols include only patients who are partial responders or non-responders, can this be considered as an accurate representation of the patient population?
      
      There was agreement amongst the panel members that it was unethical to take someone off a treatment that is working to put them in a study that may not give them relief and expose them to the risk of not doing well. Add-on trials would be easier to justify in this patient population, and would likely be more attractive to patients. "Enhanced enrollment trials" may also be conducted by screening in only those patients who show an initial response to the drug.
      
      There aren't many trials that have looked at efficacy beyond 6 months. A double blind study would not be required to go on for a year. Optimally, these trials should be conducted for up to 12 to13 weeks, accompanied by follow-up trials lasting up to one year. Acceptable trial designs would include re-randomizing responders to a placebo or drug, to monitor withdrawal and relapse. It is important to know what happens to patients when you take them off the drugs.
      
      
3. Safety Issues:
   
   
   1. Safety profiles for current standards of care for:
      
      
      • central neuropathic pain (e.g. MS)
        
        
      • are patients with DNP at a higher risk of developing certain/specific type(s) of neoplastic injuries?
        
        
   2. What are the issues surrounding risk-benefit assessments in various types of neuropathic pain with respect to differences in patient populations, age, etc?
      
      
   3. Preferred comparators (placebo, active drug) for safety assessment, short term and long term; rationale for preference if any.
      
      
   4. For each type of central or peripheral neuropathic pain trial:
      
      
      • what are acceptable concomitant medications and what are not?
        
        
      • are medications to relieve pain (e.g., Opiates, NSAID's, etc) routinely excluded in a specific type of neuropathic pain trial?
        
        
      The reasons not to use a drug are mostly related to individual circumstances rather than a class or condition issue, e.g., because of previous experience or of other health issues in an individual patient. Physicians should be aware of the patient's overall health, of effects from the underlying condition (e.g., alterations in CNS connections can lead to lower pain thresholds to many types of stimulation). The physician should use the best therapy available for that patient, as quickly as possible, and be aware of contraindications of the drugs being used. There are condition-specific instances where certain drugs should be avoided: e.g., NSAIDS should not be used for diabetic neuropathy due to renal toxicity. Pharmacologic agents must be selected carefully.
      
      With respect to opiates in these patient populations, there are concerns regarding safety issues associated with this class of drugs such as addiction, overdose, diversion, constipation , or other side effects that may aggravate autonomic conditions, etc. When using these drugs, the degree of cognitive impairment and/or degree of drowsiness must also be assessed.
      
      When used appropriately, opiates have a specific role in chronic noncancer pain situations. The key lies in how they are used, the setting of appropriate goals, determining appropriate standards for how they can be used to minimize the risks. One panel member was of the opinion that it should not be categorically stated that opiates should not be used for a specific population, but that a benefit risk ratio must be assessed individually.
      
      In diabetic neuropathy, eventually the pain burns out as the disease progresses and nerves die. Situations where pain is being relieved by a drug primarily because the treatment is accelerating the nerve damage must be avoided.
      
      In terms of comparators, three situations may be considered:
      
      
      1. consistent use of an active pain relieving drug like tricyclics as the comparator;
         
         
      2. use of a comparator drug that is considered the best at the time the trial is initiated, i.e., "best current therapy"; or,
         
         
      3. use of an agent that the physician thinks is appropriate, which is the real life situation.
         
         Panel members were not in agreement with respect to comparator trials. It was suggested by one panel member that a new anti-epileptic should be compared to the current anti-epileptic that is used in the treatment of neuropathic pain, while another indicated that they saw little advantage to that design. One panel member felt that choosing only one active comparator may be problematic particularly in diabetic patients, because of the need for individualized co-medication due to problems the patients can have with polytherapy.
         
         
      • Closing remarks, meeting adjourned - W. Pryse-Phillips

Thank you.

Meeting adjourned.