NEWS & VIEWS of progression to dementia has been suggested, which may require defining criteria for prodromal AD based on cerebrospinal fluid (CSF) or neuroimaging bio­markers. Whether such an approach will lead to better prediction of dementia is as yet unknown, but analysis of CSF or MRI bio­markers after cognitive testing has not been shown to lead to better prediction of dementia in patients with MCI. 10 Before such criteria can be applied to population settings, large studies in relevant age brackets, including people with comorbid dis­orders, are required. These studies must also take all aspects of false-positive and false-negative results into account. MCI remains a complex concept, and its causes are heterogeneous. Considering MCI as a fixed concept based on clinical criteria is a slippery slope. Some might argue that people with cognitive impairment in multiple domains and in the bottom range of the MCI spectrum—that is, those with the worst impairment—would previously have been diagnosed with minimal or mild dementia. Because of the boundary changes that occur as a result of fashions in research and clinical practice, however, these cases would now be called MCI. On the basis of the findings by Roberts et al., and previous reports from population-­ based samples, the early signs of MCI have limited sensitivity and specificity for the prediction of the development of dementia. Clearly, therefore, the value of a MCI diagnosis warrants consideration. Diagnoses should be communicated carefully in order to avoid the potential harms of diagnosing a pre-dementia state in ­i ndividuals who might never progress to dementia. Department of Neurology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands (E.R.). Department of Public Health and Primary Care, Cambridge Institute of Public Health, Cambridge University, Forvie Site, Robinson Way, Cambridge CB2 0SR (C.B.). Correspondence to: E.R. [email protected] Acknowledgements The authors thank Blossom Stephan for substantial and constructive comments. Competing interests The authors declare no competing interests. 1.


Petersen, R. C. Mild cognitive impairment as a diagnostic entity. J. Intern. Med. 256, 183–194 (2004). Vellas, B. et al. Designing drug trials for Alzheimer’s disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD





Task Force. Alzheimers Dement. 9, 438–444 (2013). Roberts, R. O. et al. Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal. Neurology 82, 317–325 (2014). Gao, S. et al. Mild cognitive impairment, incidence, progression, and reversion: findings from a community-based cohort of elderly African Americans. Am. J. Geriatr. Psychiatry j.jagp.2013.02.015. Sachdev, P. S. et al. Factors predicting reversion from mild cognitive impairment to normal cognitive functioning: a population-based study. PLoS ONE 8, e59649 (2013). Ward, A., Tardiff, S., Dye, C. & Arrighi, H. M. Rate of conversion from prodromal Alzheimer’s

disease to Alzheimer’s dementia: a systematic review of the literature. Dement. Geriatr. Cogn. Dis. Extra 3, 320–332 (2013). 7. Fox, C. et al. Screening for dementia—is it a no brainer? Int. J. Clin. Pract. 67, 1076–1080 (2013). 8. Stephan, B. et al. Optimizing mild cognitive impairment for discriminating dementia risk in the general older population. Am. J. Geriatr. Psychiatry 18, 662–673 (2010). 9. Dubois, B. et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 9, 1118–1127 (2010). 10. Richard, E. et al. MRI and cerebrospinal fluid biomarkers for predicting progression to Alzheimer’s disease in patients with mild cognitive impairment: a diagnostic accuracy study. BMJ Open 3, e002541 (2013).


Measuring abuse liability —is the risk worth taking? Eija A. Kalso and Kaarlo Simojoki

Early trials that supported short-term opioid treatment in the management of chronic non-cancer pain excluded patients at high risk of drug abuse, and might have overestimated the efficacy of this approach. The recent IMMPACT recommendations suggest inclusion of high-risk groups in future clinical trials of potentially addictive drugs. Is the risk worth taking? Kalso, E. A. & Simojoki, K. Nat. Rev. Neurol. 10, 131–133 (2014); published online 11 February 2014; doi:10.1038/nrneurol.2014.16

The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consortium convened in 2009 to develop consensus recommendations for assessing abuse liability—that is, the propensity of a drug to be susceptible to abuse (Box 1)—in analgesic clinical trials. The recently published IMMPACT recommendations on trial design1 state that to adequately assess abuse liability, at least some of the study samples should represent the population of individuals who will be exposed to the drug in practice, including patients who are at significant risk. Chronic pain—in particular, neuropathic pain—is often difficult to manage. The efficacy of opioids in the management of cancer-­related pain encouraged their use in the management of chronic non-­ cancer pain. A fervent discussion regarding whether neuropathic pain is sensitive to opioids ensued, and over the past 25 years several randomized controlled trials (RCTs), systematic reviews and clinical guidelines have addressed the topic.2 Current evidence suggests that opioids


have short-term benefit in management of neuropathic pain and osteoarthritisrelated pain, and the European Federation of Neurological Societies guidelines recommend opioids as second-line pharmacological therapy for the management of neuropathic pain.3 In the Western world, ­o steoarthritis pain and lower back pain constitute a larger market for opioids than does cancer pain. Indeed, the past 10 years have seen a twofold to threefold increase in the use of prescription opioids in the USA and Canada, and opioid use is also rapidly increasing in Europe. 4 According to the Centers for Disease Control and Prevention, in the USA, prescription opioids currently account for a higher proportion of overdose mortality than does heroin. As a consequence, regulation agencies, such as the State of Washington in the USA, have imposed restrictions on prescription of opioids. Several screening tools have been developed to identify patients who are at risk of opioid abuse; however, limitations for their clinical use have now been VOLUME 10  |  MARCH 2014  |  131

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NEWS & VIEWS identified and, most importantly, these tools have not been validated in larger ­clinical settings.5 The IMMPACT recommendations come in the wake of the 2010 FDA recommendations for assessment of the abuse potential of drugs for the pharmaceutical industry.6 The FDA focused on preclinical and human laboratory studies, but they also made a number of recommendations for clinical trials including drugs with abuse potential. First, they recommended that retrospective trials should apply standardized reporting of adverse effects related to euphoria and withdrawal. Second, they recommended that the investigators should report in detail cases of abuse, misuse, diversion and study drop-outs. Last, they recommended that the investigators should provide information about the risk of abuse, diversion, overdose and addiction in the study population (see Box 1 for definitions). The IMMPACT recommendations1 focus on three domains in clinical trials assessing abuse liability: characterization of baseline risk of the study sample, relevant trial design features, and outcome measurement. Box 1 | Definitions Aberrant drug-related behaviour Behaviour that deviates from the agreedon treatment plan; usually the first sign of upcoming problems but does not per se imply abuse or addiction5 Abuse Substance misuse (see below) with harmful consequences5 Abuse liability The propensity of a substance to make the user susceptible to social, psychological, or physical problems (WHO Lexicon of alcohol and drug terms) Addiction Loss of control over drug use, often in the presence of tolerance, and withdrawal on discontinuation Diversion Obtaining or distributing a legitimately distributed, controlled substance via illegal channels or methods5 Misuse Use of a medication for nonmedical purpose or in a manner that does not adhere to legal or medical guidelines, with potentially harmful consequences5 Physical dependence A state in which discontinuation or reduction of a substance results in withdrawal syndrome5 Please see the source5 of these definitions for further studies

132  |  MARCH 2014  |  VOLUME 10

The baseline risks of the patients include prior opioid, alcohol or any other substance abuse, smoking history and presence of depression or psychiatric disorders. A family history of substance abuse can also be a factor. Despite established guidelines, which advocate caution when considering prescription of opioids for individuals who are at high risk of opioid abuse, epidemiological studies suggest that long-term treatment (over 90 days) with high doses of opioids has been prescribed to patients at risk.7 In these cases, assessment of potential risk was based mainly on clinical experience, and included measures such as previous drug abuse, mental health problems and young age.8 It should also be noted, however, that assessing the risk of drug abuse for the purpose of performing a clinical trial is different from the clinical setting. In a clinical trial, the patients are managed according to the trial protocol, whereas in a clinical setting, pain m ­ anagement is tailored to the individual patient. Possible opioid therapy in patients at high risk should be evaluated in the context of a multidisciplinary pain clinic. The higher the risk of abuse, the more careful the consideration of the risk–benefit ratio should be. Furthermore, if a patient with pain and psychiatric comorbidity is considered for opioid therapy, the adequacy of the current treatment of the psychiatric disorder should be evaluated before initiating the opioid therapy. Patients at high risk should also be offered concomitant cognitive behavioural therapy, which has been shown to reduce opioid dose escalation and improve pain management.9 Opioids were introduced to the manage­ ment of non-cancer pain after positive results from RCTs, which excluded patients at presumed risk of addiction. The problems with abuse liability were officially identified only when large epidemiological studies were published. Furthermore, the early RCTs had short follow-up times (4–60 days) and used the ‘last observation carried forward’ method, meaning that if the patient dropped out of the trial, the last pain intensity measure was used for the missing time points. Many studies might thus have overestimated opioid efficacy. As reviewed in 2013, only a minority of patients achieve long-term (months to years) benefits from opioid therapy, and up to 50% of patients discontinue the treatment due to adverse effects and/or ­inadequate pain relief.10

Studies using modern criteria for trial design and outcome (at least 50% pain relief or no more than mild pain) suggest that opioids are no better than placebo for the relief of osteoarthritis or chronic lower back pain.10 This finding does not mean that opioids have no effect, but that only a few patients achieve meaningful pain relief, which necessitates careful consideration of the potential risks and benefits.


The higher the risk of abuse, the more careful the consideration of the risk–benefit ratio should be


Research into alternatives to opioids for pain relief has identified the endocannabin­ oid receptor agonists as potential targets. The caveat is that cannabinoid receptor CB1 is expressed in the brain’s reward circuit, meaning that the CB1 agonists are potentially addictive. Therefore, assessment of abuse liability remains important, even in future trials focusing on nonopioid analgesia. To conclude, opioids should preferably be used for a predetermined duration only, although long-term opioid therapy can be warranted in exceptional cases. Given that the expected benefit of long-term opioid treatment can be small and difficult to predict, it seems unethical to recruit patients to clinical trials who are at high risk of abuse of the drugs being investigated. The abuse liability for each drug can be tentatively assessed using animal models of drug reinforcement and dependence, and the abuse liability estimates can be confirmed in smaller-scale human experimental studies. This method has been successfully used to assess the abuse liability of monobuprenorphine as part of the process of bringing a buprenorphine–naloxone combination to clinical use. Finally, epidemiological studies that assess the abuse risk after the drug has been released for the market remain important. Assessing the formulation-specific (for example, fast-acting intranasal administration versus slow-release transdermal patches) abuse potential of a given drug is easier than predicting the risk for the individual patient. To curb the complex and growing problems related to non­medical use of drugs, active multi­disciplinary collaboration is needed to bring together the cutting-edge knowledge of pain management and addiction research. Registration

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NEWS & VIEWS trials of drugs with abuse potential require large cohorts of patients and long followup times. The chance of adverse consequences is too high to warrant recruitment of patients at high risk. Pain Clinic, Helsinki University Central Hospital, Haartmaninkatu 2A, P. O. Box 140, Helsinki, 00029 HUS, Finland (E.A.K.). A-Clinic Foundation, Leppävaarankatu 10, 00260 Espoo, Finland (K.S.). Correspondence to: E.A.K. [email protected] Competing interests The authors declare no competing interests. 1.

O’Connor, A. B. et al. Abuse liability measures for use in analgesic clinical trials in patients with pain: IMMPACT recommendations. Pain 154, 2324–2334 (2013). 2. Chou, R. et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J. Pain 10, 113–130 (2009). 3. Attal, N. et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur. J. Neurol. 17, 1113–e88 (2010). 4. Fischer, B., Jones, W., Krahn, M. & Rehm, J. Differences and over-time changes in levels of

prescription opioid analgesic dispensing from retail pharmacies in Canada, 2005–2010. Pharmacoepidemiol. Drug Saf. 20, 1269–1277 (2011). 5. Sehgal, N., Manchikanti, L. & Smith, H. S. Prescription opioid abuse in chronic pain: a review of opioid abuse predictors and strategies to curb opioid abuse. Pain Physician 15, ES67–ES92 (2012). 6. Guidance for industry: assessment of abuse potential of drugs. [online], GuidanceComplianceRegulatoryInformation/ Guidances/UCM198650.pdf (2010). 7. Edlund, M. J. et al. Trends in use of opioids for chronic noncancer pain among individuals with mental health and substance use disorders: the TROUP study. Clin. J. Pain 26, 1–8 (2010). 8. Eriksen, J., Sjøgren, P., Bruera, E., Ekholm, O. & Rasmussen, N. K. Critical issues on opioids in chronic non-cancer pain: an epidemiological study. Pain 125, 172–179 (2006). 9. Naylor, M. R., Naud, S., Keefe, F. J. & Helzer, J. E. Therapeutic Interactive Voice Response (TIVR) to reduce analgesic medication use for chronic pain management. J. Pain 11, 1410–1419 (2010). 10. Moore, A., Derry, S., Eccleston, C. & Kalso, E. Expect analgesic failure; pursue analgesic success. BMJ 346, f2690 (2013).


Imaging the epileptic brain —time for new standards Neda Bernasconi and Andrea Bernasconi

Therapeutic management of patients with epilepsy is often challenging, particularly in those who are pharmacoresistant. In these patients, the only option to control seizures is elective surgery. Optimization of MRI acquisition sequences might mean early identification of patients, thereby speeding up surgical intervention. Bernasconi, N. & Bernasconi, A. Nat. Rev. Neurol. 10, 133–134 (2014); published online 14 January 2014; doi:10.1038/nrneurol.2013.280

Epilepsy is one of the most prevalent chronic neurological disorders. In more than onethird of patients, pharmacotherapy does not result in freedom from seizures. MRI is essential to detect the structural anomaly associated with the epileptogenic zone and, in patients who exhibit such anomalies, resective surgery is the only effective treatment. On average, two decades will have passed before a patient is finally referred to a tertiary centre to evaluate their candidacy to undergo epilepsy surgery.1 During this period, numerous unsuccessful attempts might have been made to arrest the seiz­ures pharmacologically. Uncontrolled epilepsy markedly affects patients’ quality of life, and has devastating effects on cognitive function. Importantly, seizures are harmful to the

brain, and their frequency correlates with increased risk of injury and sudden death. These findings, as well as the long-term socioeconomic con­s equences of uncontrolled epilepsy, emphasize the need for early ­diagnosis and effective surgical therapy.2 In a new paper published in Epilepsia, Wellmer et al. propose a protocol comprising six MRI sequences to identify epileptogenic lesions at an early stage in the outpatient setting. 3 On the basis of an evalu­ation of 2,740 patients who were examined in a single tertiary centre between 1989 and 2009, the protocol consists of a T1-weighted sequence yielding isotropic images with a voxel size of 1 mm3, as well as T2-weighted, fluid-attenuated inversion recovery (FLAIR) and axial h ­ aemosiderin/


calcification-sensitive sequences. For the T2-weighted and FLAIR sequences, the authors recommend images with a slice thickness of 3 mm or less, angulated both perpendicular and parallel to the long axis of the hippocampus. This proposed protocol, which follows other recent recommendations,4,5 has the advantage of encompassing a large cohort of patients with a spectrum of lesion types, such as hippocampal sclerosis, tumours and various types of cortical malformations. However, the study was based on retrospective evaluation of radiological reports rather than an independent review of the actual images. In addition, the proposed sequences might be biased by the experience and preferences of the various in-house radiologists during the previous 20 years. For instance, poor diagnostic suitability to detect mesiotemporal sclerosis is ascribed to the T1-weighted sequence, which has long been valued for both visual and quantitative diagnosis of this entity. Current trends in medical imaging emphasize the use of objective, evidencebased criteria to assess sensitivity and speci­ ficity. Essential features in the design of quality studies, such as clear definitions of the diagnostic criteria, blinded review, and independent tests to assess reliability, have been proposed by the International League Against Epilepsy, with the aim of achieving global harmonization, and to facilitate replication in studies.6 A consensus published in 2013 on the histopathological classification of hippocampal sclerosis in temporal lobe epilepsy is a good example of such b ­ eneficial synergies.7 The proposed imaging parameters, 3 which are in line with the routine clinical radiological assessment of patients currently carried out in many institutions, are mainly suitable for the visual detection of large to medium-sized lesions. For the T2-weighted and FLAIR sequences, Wellmer et al. did not mention the optimal in-plane resolution, a key factor when searching for subtle lesions. To achieve inplane reso­lutions ≤1 mm on a 1.5 T scanner, one must either reduce the size of the field of view, thereby sacrificing whole-brain coverage, or introduce inter-slice gaps and risk missing potentially anoma­lous tissue. This risk holds true particularly with respect to mesiotemporal sclerosis and focal cortical dysplasia, the two most common lesions in drug-resistant epilepsy. Now a d ay s , b e s t - pr a c t i c e M R I i s unremark­­able in ~20–50% of referrals to VOLUME 10  |  MARCH 2014  |  133

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Clinical trials: Measuring abuse liability--is the risk worth taking?

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