Smoked cannabis for chronic neuropathic pain: a randomized controlled trial

Mark A. Ware; Tongtong Wang; Stan Shapiro; Ann Robinson; Thierry Ducruet; Thao Huynh; Ann Gamsa; Gary J. Bennett; Jean-Paul Collet

doi:10.1503/cmaj.091414

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Statistical Significance is not the same as Significance
Jacob ED Levman

Published on: 16 November 2010
Reporting P-values in Clinical Research: Time for a Significant Change
Jacquelyn J. Cragg

Published on: 18 October 2010
Risk of psychosis with medicinal cannabis use
Christine Miller

Published on: 07 September 2010

Published on: (16 November 2010)

Statistical Significance is not the same as Significance
Jacob ED Levman, Toronto, Ont.
The recent interesting and beneficial article by Ware et al. [1] has been followed up with a response letter regarding the use of statistical testing [2]. This follow-up letter correctly points out that statements such as “nonsignificant degrees of relief” and “higher but not significant”, are both common in the medical literature and should be avoided [2].
I agree with the points made by Cragg [2], however, I...
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The recent interesting and beneficial article by Ware et al. [1] has been followed up with a response letter regarding the use of statistical testing [2]. This follow-up letter correctly points out that statements such as “nonsignificant degrees of relief” and “higher but not significant”, are both common in the medical literature and should be avoided [2].
I agree with the points made by Cragg [2], however, I feel that the clinical readership could benefit from an even simpler explanation of why statements such as “higher but not significant” should be avoided.
The word ‘significant’ is qualitative. Any individual researcher or clinician is able to decide for themselves what constitutes a ‘significant’ effect. The word ‘significance’ is not synonymous with the term ‘statistical significance’. Statistical significance is typically defined as a p-value below 0.05, which means that there is a less than 5% probability that the observed data occurred due to random chance. Experimental data that achieves ‘statistical significance’ would not necessarily be qualitatively described as significant. Furthermore, experiments with very few samples may yield a qualitatively significant effect that does not achieve statistical significance.
Thus, in the literature, the words ‘statistical significance’ should not be replaced with the word ‘significance’ as it can lead to confusion due to the different meanings of the terms.
Jacob Levman, PhD (Medical Biophysics, University of Toronto)
[1] Ware et al., “Smoked cannabis for chronic neuropathic pain: a randomized controlled trial” Canadian Medical Association Journal (2010) 182:E694-701E.
[2] Cragg, “Reporting P-values in Clinical Research: Time for a Significant Change,” Canadian Medical Association Journal (2010) Reply to 182:E694-701E.
Conflict of Interest:
None declared
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Competing Interests: None declared.
Published on: (18 October 2010)

Reporting P-values in Clinical Research: Time for a Significant Change
Jacquelyn J. Cragg, Vancouver, BC
I write in response to the well-written and well-supported paper “Smoked cannabis for chronic neuropathic pain: a randomized controlled trial.” The reporting I found troubling, which has become a trend in medical literature was: “preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief.”
This commonly misused phraseology of “higher but not significant” or “lower but no...
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I write in response to the well-written and well-supported paper “Smoked cannabis for chronic neuropathic pain: a randomized controlled trial.” The reporting I found troubling, which has become a trend in medical literature was: “preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief.”
This commonly misused phraseology of “higher but not significant” or “lower but not significant” represents a deep misunderstanding of confidence intervals and p-values. Clinicians, it is time for a significant change in reporting ‘significant’ and ‘non-significant’ results. Statisticians, generally interested in reading your papers, will stop reading after statements like these.
In clinical studies, we are most often interested in the difference between two group means. We then report a confidence interval for the difference and the associated p-value. What does this confidence interval mean? We recognize that we estimate the population (true) difference not by a single value, but rather by an interval which is likely to capture the population mean. The point estimate we obtain, therefore, merely represents the middle of the interval; the actual estimate of the population value is best thought of as a range of values. We ought not be too concerned with the point estimate; it will be different every time we repeat the experiment. Given this idea, when comparing two means, it does not make much sense to compare two means simply by comparing their point estimates- rather, we are really comparing a range of values to another ranges of values. So we cannot say meaningfully that “mean x was higher than mean y but not significantly different”. In this case, the statistical test says that essentially, the ranges of possible values are too similar to each other to be considered different.
And one last thing while I have your statistical attention- clinicians often report “mean x was higher than mean y, but it did not reach significance,”
This really is reaching.
If you want to refrain from making the statisticians in a conference hall cringe, avoid phrases like “higher but not significant” or a “trend toward significance” or “reaching significance”.
There are really no such things.
Conflict of Interest:
None declared
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Competing Interests: None declared.
Published on: (7 September 2010)

Risk of psychosis with medicinal cannabis use
Christine Miller, Baltimore, MD
The recent report on cannabis-induced reduction of neuropathic pain by Ware et al. (CMAJ August 30, 2010) received much attention by the press. Unfortunately, in their media interviews, the authors failed to adequately emphasize that the reduction in neuropathic pain was modest as compared to other drugs and efficacy was only demonstrated at the highest dose, along with side effects.
Of particular concern in...
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The recent report on cannabis-induced reduction of neuropathic pain by Ware et al. (CMAJ August 30, 2010) received much attention by the press. Unfortunately, in their media interviews, the authors failed to adequately emphasize that the reduction in neuropathic pain was modest as compared to other drugs and efficacy was only demonstrated at the highest dose, along with side effects.
Of particular concern in regard to side effects, paranoia was experienced at the highest dose by one subject and “racing thoughts’ by the same or another subject (Table 4 ), an outcome not discussed by the authors either in their press release or in their CMAJ publication. Why is this important? Paranoia is frequently a prodromal symptom of a psychotic disorder[1-3]. There is now an abundant body of literature demonstrating that cannabis use increases the risk of psychotic disorders by approximately 2-fold in the general population[4-6] and by at least 4- fold in those with a family history of psychosis (either first or second degree relatives)[7,8]. The prospective study by Henquet et al.[4] demonstrated that the relationship is causal. Yet other studies have indicated a dose response, in that high strength cannabis conveys a proportionately higher risk of a psychotic outcome[9]. In view of the fact that no treatment yet exists that can cure the psychotic disorders of schizophrenia and psychotic bipolar disorder, it is probable that in susceptible individuals, cannabis use can make the difference between living a psychologically normal life and not.
What are the odds that an individual would develop a full-blown psychotic disorder whether or not they were a study participant? The incidence of psychotic disorders in the general population has been shown to be roughly 35 per 100,000 person-years[10,11]. Assuming that the time frame of the Ware et al. study was 4 x 14 days, the number of study participants required to see the development of one psychotic disorder during that time would be greater than 18,000, close to 1000-fold more than the small number of actual participants(23).
Hopefully, the paranoia experienced by the study participant was transient, but the individual should be warned about the potentially serious implications for continued cannabis use given this experience.
1.Gourzis P, Katrivanou A, Beratis S. Symptomatology of the initial prodromal phase in schizophrenia. Schizophr Bull. 2002;28(3):415-29.
2.Bechdolf A, Ruhrmann S, Wagner M, Kühn KU, Janssen B, Bottlender R, Wieneke A, Schulze-Lutter F, Maier W, Klosterkötter J.Interventions in the initial prodromal states of psychosis in Germany: concept and recruitment.Br J Psychiatry Suppl. 2005;48:s45-8.
3.Cannon TD, Cadenhead K, Cornblatt B, Woods SW, Addington J, Walker E, Seidman LJ, Perkins D, Tsuang M, McGlashan T, Heinssen R. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry. 2008;65(1):28-37.
4.Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ. 2005;330:11–15.
5.Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319–328.
6.McGrath J, Welham J, Scott J, Varghese D, Degenhardt L, Hayatbakhsh MR, Alati R, Williams GM, Bor W, Najman JM. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen Psychiatry. 2010; 67(5):440-7.
7.McGuire PK, Jones P, Harvey I, Williams M, McGuffin P, Murray RM. Morbid risk of schizophrenia for relatives of patients with cannabis- associated psychosis. Schizophr Res. 1995,15(3):277-81.
8.Arendt M, Mortensen PB, Rosenberg R, Pedersen CB, Waltoft BL. Familial predisposition for psychiatric disorder: comparison of subjects treated for cannabis-induced psychosis and schizophrenia. Arch Gen Psychiatry. 2008;65(11):1269-74.
9.Di Forti M, Morgan C, Dazzan P, Pariante C, Mondelli V, Marques TR, Handley R, Luzi S, Russo M, Paparelli A, Butt A, Stilo SA, Wiffen B, Powell J, Murray RM. High-potency cannabis and the risk of psychosis. Br J Psychiatry. 2009,195(6):488-91.
10.Kirkbride JB, Fearon P, Morgan C, Dazzan P, Morgan K, Tarrant J, Lloyd T, Holloway J, Hutchinson G, Leff JP, Mallett RM, Harrison GL, Murray RM, Jones PB. Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center AeSOP study. Arch Gen Psychiatry. 2006; 63(3):250-8.
11.van Os J, Linscott RJ, Myin-Germeys I, Delespaul P, Krabbendam L. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. Psychol Med. 2009;39(2):179-95.
Conflict of Interest:
None declared
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Competing Interests: None declared.

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