The Journal of Pain, Vol 16, No 2 (February), 2015: pp 116-123 Available online at www.jpain.org and www.sciencedirect.com A Review of the Use of the Number Needed to Treat to Evaluate the Efficacy of Analgesics Nathaniel Katz, Florence C. Paillard, and Richard Van Inwegen Analgesic Solutions, Natick, Massachusetts. Abstract: Standardized measures of efficacy are needed to compare analgesic efficacy across trials. The number needed to treat (NNT) is considered a statistically robust and readily interpretable mea- sure to rank the efficacy of treatments, including analgesics. The NNT has become widely utilized to compare the efficacy of chronic pain treatments, helping physicians make treatment decisions and informing decisions for market access, reimbursement, and treatment guidelines. However, the NNT is associated with specific weaknesses in calculation and interpretation not associated with other methods for integrating trial data. These weaknesses include distortions in calculation as placebo effects approach treatment effects, with the possibility of infinite values; difficulties in esti- mating the NNT’s confidence interval; and difficulties in interpretation. The NNT also requires select- ing cutoffs of the original variable for dichotomization, with the NNT often changing depending on the cutoff. The NNT also suffers from problems common to other placebo-adjusted endpoints, including being sensitive to study-related and external factors (eg, year of publication). Therefore, clinicians and other stakeholders need to be aware of these issues to correctly calculate, use, and interpret the NNT. Nevertheless, efficacy, as measured by any variable, is only one aspect of a treat- ment to be considered in determining its place in therapy. Perspective: The NNT has become widely utilized to compare the efficacy of chronic pain treatments. This article reviews the uses of the NNT and the potential problems associated with its calculation, use, and interpretation. Clinicians should be aware of these issues when interpreting clinical trial data based on the NNT. ª 2015 by the American Pain Society Key words: Number needed to treat, analgesics, efficacy, clinical trials, chronic pain treatment. he number needed to treat (NNT) was devised in mean value for the primary endpoint. The group mean 1988 by Laupacis et al29 as a single unitary measure difference is often difficult to interpret in a clinically Tof a drug’s efficacy that was meant to provide an intuitive manner. Thus, to allow easier interpretation of intuitive means for evaluating the relative efficacy of clinical data, the NNT defines each patient as either a different drugs in order to rank them as to their effi- responder or a nonresponder (based on some predefined cacy.33 Like any other method that evaluates the relative definition of response) and compares the proportion of efficacy of treatments, the NNT is dependent on responders in each group. comparing data across randomized double-blind controlled trials, the gold standard in clinical research. The efficacy of the drug being studied is measured as in- Definition and Methods of Calculation of cremental benefit above that in the placebo group and is the NNT typically quantified by the difference between groups in The NNT is interpreted as the number of patients one would need to treat in order to get one more responder on the active treatment than one would have gotten had The authors received a grant from Janssen Pharmaceuticals to support they been treated with control. In technical terms, the independent writing of this review. The authors declare having no financial relationship to the work. N.K. NNT is the inverse of the absolute risk difference (ARD): and R.V.I. are employees and F.C.P. is a contractor of Analgesic Solutions. ¼ 1 : NNT ARD Address reprint requests to Florence C. Paillard, PhD, Analgesic Solutions, ARD is the difference in proportion of patients who 232 Pond St, Natick, MA 01760. E-mail: [email protected] 1526-5900/$36.00 manifest a response to a treatment and the proportion ª 2015 by the American Pain Society of patients who manifest a response to control. It is http://dx.doi.org/10.1016/j.jpain.2014.08.005 possible to use placebo, nontreatment, or another active 116 Katz, Paillard, and Van Inwegen The Journal of Pain 117 treatment as the control to calculate the NNT. The choice the lives of countless patients. Reliance on the NNT for of controls has a huge impact on the NNT values and this purpose is based on presumptions of methodologic their interpretations. Thus, any comparison of NNT robustness and straightforward interpretability. values must use the same controls for calculations; Herein, we conducted a qualitative review of the comparing NNT values calculated with different control advantages and limitations of the NNT to assess whether groups would not be valid. Therefore, the discussions the NNT is suitable for evaluating the comparative effi- in this review are limited to comparisons to placebo con- cacy of analgesics for chronic pain. trols, unless otherwise so stated. Most often, the response used to calculate the ARD is an improvement Critiques of the NNT (eg, reduction in pain), in which case ARD is calculated as ‘‘response with drug minus response with placebo.’’ Critiques of NNT have been grouped into 6 major Responders, patients who manifest a response, are categories (Table 1). A number of these critiques (both defined as patients who meet a predefined criterion of positive and negative) were not specifically inherent to response in an all-or-nothing fashion (ie, death/life). How- the NNT, but could be applied to any comparative mea- ever, for most uses, a nondichotomous endpoint is used sure of efficacy such as the ARD and OR. The fact that (eg, pain intensity score), and a predefined response crite- the NNT can be impacted by study design (eg, study rion is created (eg, having a $30% pain reduction or not). size, number of arms, type of comparator) and subject’s The following is an example of calculating the NNT. If characteristics (eg, indication, severity, and duration of 14,31,32,48,51 half (50%) the patients on active treatment respond disease; reviewed in references ) is not too (response rate = .5), and one quarter (25%) of the surprising as these factors influence the response rate, placebo-treated patients respond (response rate = .25), which forms the basis of the NNT definition. These then the ARD is .5À.25 = .25. The NNT is 1/.25 = 4. This variables can also influence other comparative can be interpreted as 4 patients would have to be treated measures. Thus, critiques of the NNT were categorized with the treatment to get 1 more responder than with based on whether they are specific to the NNT or placebo. In other words, treating 4 patients with treat- nonspecifically applicable to any placebo-adjusted ment would yield 2 responders, whereas treating 4 efficacy measure used in meta-analysis. patients with placebo would yield only 1 responder. The NNT can be also calculated using the odds ratio Critiques Specific to the NNT (OR) or the relative risk reduction (RRR) (reviewed in33). The optimal NNT value is 1, whereby every patient has Issues Associated With Calculating the NNT a positive response to treatment and no patient responds Calculating the Combined NNT From Various Trials Can to placebo. When a drug produces an identical effect to Be Subject to Bias. Two methods have been proposed placebo, the NNT would have a value of infinity (ARD = 0 and used to calculate the NNT from several clinical trials. and NNT = 1/0). Thus, in theory, the NNT can vary from 1 One method uses a meta-analytic method wherein each to infinity. It is also possible for the NNT to have a nega- trial is handled separately, and the other treats the data tive value when the response rate for placebo is greater as if arising from a single trial.2,6 The latter method is than that for the drug. In practice, the NNT is usually used prone to bias, especially when there is an imbalance in to compare effective drugs, so negative and infinity sample size between treatment and placebo arms, a values are not usually reported because the drug is phenomenon called the Simpson’s paradox. The meta- considered ineffective. Thus, the lower (ie, the closer to analytic method is not prone to this issue. In meta- 1) the NNT, the more efficacious the drug. analyses, the use of a relative measure such as OR or risk ratio (RR) is advocated because event rates vary considerably from study to study even for the same Uses of the NNT drug.6 The method used to calculate the combined NNT The NNT is usually used to compare the efficacy of from various trials should be clearly stated. different drugs for the same indication to enable physi- The NNT Can Have an Infinite Value. Unlike other cians to make informed choices in clinical practice. To measures of efficacy (eg, ARD), the NNT is an inversion allow comparison and ranking of the efficacy of different of a response (ie, 1/ARD) so that a zero difference treatments, many systematic reviews and meta-analyses between active and placebo groups results in an unde- of randomized controlled trials provide average NNT fined number (ie, 1/0).18,26,43 This could be further values for various treatments across an indication (the complicated if the treatment in one study is less NNT being treatment- and dose-specific).33 For instance, efficacious than placebo, resulting in a negative number. a meta-analysis evaluating the efficacy of analgesics Having an infinite or negative value renders ranked the drugs’ efficacy by NNT value (the lower the comparing studies and calculating the combined NNT NNT, the higher the efficacy) as follows: efficacy of for several trials difficult.2,8,22,30,50 As stated above, ibuprofen 400 mg (NNT = 2.8) > paracetamol (600/ using a meta-analytic methodology based on the OR or 650 mg) (NNT = 5.0) > codeine 60 mg (NNT = 18).34 RR is recommended.6 The NNT has become widely utilized for comparing In some systematic reviews, the NNT is considered treatment efficacy for chronic pain and other conditions, ‘‘nonsignificant’’ when it is high or infinite,16 which which informs decisions for market access, reimburse- means that the treatment has no therapeutic value.