Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial

May combine two claims.

Nabilone improved quality of life (HIT-6 and SF-36) in patients with medication overuse headache, whereas ibuprofen did not.

“moreover, nabilone was the only drug able to reduce the level of medication dependence (−41 %, p < 0.01) and to improve the quality of life (p < 0.05).”

• Also stated in: § Results · plain

  “In addition, the quality of life indicators changed with nabilone, but not with ibuprofen: a significant improvement was seen in SF-36 Scale (for both physical and mental components) and HIT-6™ Scales (Table 2).”

• Also stated in: § Discussion · plain

  “The slight improvements in the quality of life (in HIT-6™ and SF-36), were recorded only with nabilone and not with ibuprofen (Table 3);”

May combine two claims.

Improvements with ibuprofen compared to baseline occurred only in subjects taking ibuprofen during the first period, not the second.

“A deeper analysis showed that the improvements compared to baseline recorded with ibuprofen only occurred in subjects taking ibuprofen during the first period of treatment (i.e. DRUG A), but not in subjects taking ibuprofen during the second period of treatment (i.e. DRUG B).”

May combine two claims.

Nabilone reduced the level of medication dependence (LDQ) in patients with medication overuse headache, whereas ibuprofen did not.

“moreover, nabilone was the only drug able to reduce the level of medication dependence (−41 %, p < 0.01) and to improve the quality of life (p < 0.05).”

• Also stated in: § Results · plain

  “Nabilone was directly superior to ibuprofen in reducing DAI, pain intensity and the level of dependence (Table 1; Fig. 2).”

• Also stated in: § Discussion · plain

  “The questionnaire indicated a significant reduction in the level of dependency compared to baseline during treatment with nabilone (−42.2 %; p < 0.01), but not with ibuprofen (Table 1).”

May combine two claims.

The highest DAI values were in patients overusing combination medications, followed by NSAIDs and triptans, without significant differences between drugs.

“The highest DAI values were observed in those subjects in whom CM (2.8 ± 1.67) was the main overused drug, followed by NSAIDs (1.7 ± 1.03) and then triptans (1.6 ± 0.69), without statistical significant differences between the drugs.”

May combine two claims.

Nabilone reduced DAI in both single-drug overusers and multi-drug overusers, whereas ibuprofen did not reduce DAI in multi-drug overusers to the same extent.

“During the treatment with nabilone, but not with ibuprofen, the DAI dropped regardless of the type of overuse, for both SDO and MDO patients (Fig. 3).”

• Also stated in: § Discussion · plain

  “In addition, a deeper analyses showed significant differences between the DAI in single drug overusers and in multi drug overusers: during treatment with nabilone both SDO and MDO improved in a similar way, however, this was not so for the period of treatment with ibuprofen as MDO patients maintained higher overuse than SDO (Fig. 3).”

May combine two claims.

Multi-drug overusers had higher DAI than single-drug overusers at baseline and throughout the study except during nabilone treatment.

“The MDO group had far higher DAI values than the SDO group: 2.61 ± 1.6 versus 1.60 ± 0.79, respectively (p < 0.05). This difference in the consumption rate between the two groups of overusers persisted at each visit. We always observed higher DAI values in the MDO group (p < 0.05), however, this did not occur during the period of treatment with nabilone.”

May combine two claims.

Adverse events were mild and disappeared after discontinuation or spontaneously; no changes in blood pressure, heart rate or body weight occurred.

“All the adverse events (Table 4) were of a mild intensity and disappeared after discontinuation of the medication or spontaneously after a few days of treatment.”

• Also stated in: § Safety · plain

  “Throughout the entire study, there were no changes in blood pressure, heart rate or body weight.”

• Also stated in: § Abstract · plain

  “Side effects were uncommon, mild and disappeared when nabilone was discontinued.”

May combine two claims.

Post-treatment improvements persisted at follow-up 2 weeks after discontinuation, but only in patients who received nabilone during the last treatment period (carry-over effect) for HI, DAI, VAS, HIT-6.

“As far as the post-treatment results are concerned (recorded at the follow-up visit, 2 weeks after discontinuation of the DRUG B), the improvements compared to baseline persisted. However, these improvements depended on the sequence of the pharmacological treatments since, compared to baseline, only patients receiving nabilone during the last 2 months maintained a significant prolonged improvement”

• Also stated in: § Results · plain

  “The post-treatment improvements occurred only in patients who received nabilone during the second period of treatment”

Probably not a substantial claim: may not pass S3 (load-bearing).

The LDQ score at baseline was similar to that in a previous study on chronic daily headache patients.

“The LDQ score showed a high baseline value, of about 16 points and was similar to the score obtained in a previous study on patients suffering from chronic daily headaches [28].”

• cites [28] Ferrari A, Cicero AF, Bertolini A et al (2006) Need for analgesics/drugs of abuse: a comparison between headache patients and addicts by the Leeds Dependence Questionnaire (LDQ). Cephalalgia 26:187–193 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Nabilone reduced DAI from baseline by 57.7% (p < 0.01) and ibuprofen by 36.2% (p < 0.01).

“DAI dropped during both treatments: −36.2 % with ibuprofen (p < 0.01) and −57.7 % with nabilone (p < 0.01), which was significantly superior to ibuprofen, in reducing analgesic intake (DAI = 0.89 ± 0.5 and 1.34 ± 0.9, respectively, p < 0.05).”

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). May combine two claims.

Headache frequency improved only slightly with treatment, and nabilone was not significantly superior to ibuprofen on headache frequency.

“The frequency of headache had only very small improvements, probably due to the short period of treatment.”

• Also stated in: § Conclusions · hedged

  “The number of days with headache was not significantly reduced in the same way as the other indicators, probably due to the short duration of the study.”

• Also stated in: § Results · plain

  “Both drugs showed improvements in all outcomes, but nabilone was always more effective than ibuprofen, with statistically significant differences in DAI, VAS and LDQ values”

May combine two claims.

At baseline, patients had high analgesic intake (DAI 2.1 ± 1.4) and high level of drug dependence (LDQ 15.9 ± 6.3).

“At baseline, on average, the patients enrolled had a high analgesic intake (DAI 2.1 ± 1.4) and a high level of drug dependence (15.9 ± 6.3), according to the LDQ score (Fig. 2).”

May combine two claims.

Nabilone reduced VAS pain intensity from baseline by 27.9% (p < 0.01) and ibuprofen by 17.8% (p < 0.01).

“The mean intensity of pain (measured using the VAS) dropped significantly (p < 0.01) both with nabilone (−27.9 %) and with ibuprofen (−17.8 %), with a difference between the two treatments in favour of nabilone (p < 0.05).”

May combine two claims.

The enrolled patients had long-standing medication overuse headache and had failed multiple previous treatments.

“The enrolled patients in the past performed many therapeutic attempt to withdraw daily analgesic abuse, without any clinical benefits.”

• Also stated in: § Discussion · plain

  “We studied a group of patients who had been suffering from MOH for a long time (on average more than 12 years) and who had used various pharmacological and other approaches, without achieving any positive results.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A high percentage of patients with chronic daily headache at high risk to develop medication overuse headache met DSM-IV criteria for substance abuse, and prevalence of dependence varied with type of analgesic overused.

“A high percentage of patients with chronic daily headache with a high risk to develop MOH met the criteria for substance abuse according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). They also demonstrated that the prevalence of dependence according to DSM-IV varied with the different types of analgesic being overused [9].”

• cites [9] Fuh JL, Wang SJ, Lu SR, Juang KD (2005) Does medication overuse headache represent a behavior of dependence? Pain 119:49–55 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Cannabinoids act on brain reward pathways; CB1 receptors are co-localized with opioid receptors on dopaminergic cells of the nucleus accumbens.

“Cannabinoids, like many analgesics and recreational drugs, act on the brain’s reward pathways. Cannabinoid-1 receptors (CB1R) are co-localized with the opioid receptors on the dopaminergic cells of the nucleus accumbens, probably the most important structure in human reward pathways, which partly overlaps the antinociceptive pathways [30–32].”

• cites [30] Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564 sourceNot checked yet

  Not checked in the free run.

• cites [31] Devane WA, Hanus L, Breuer A et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949 sourceNot checked yet

  Not checked in the free run.

• cites [32] Greco R, Gasperi V, Sandrini G et al (2010) Alterations of the endocannabinoid system in an animal model of migraine: evaluation in cerebral areas of rat. Cephalalgia 30:296–302 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Oral cannabinoids avoid concentration peaks and with chronic administration, individual differences in bioavailability are overcome.

“The oral cannabinoids administration, on the other hand, avoids concentration peaks and with chronic administration, the individual differences in bioavailability are overcome [23, 33].”

• cites [23] Williamson EM, Evans FJ (2000) Cannabinoids in clinical practice. Drugs 60:1303–1314 sourceNot checked yet

  Not checked in the free run.

• cites [33] Karschner EL, Darwin WD, McMahon RP et al (2011) Subjective and physiological effects after controlled Sativex and oral THC administration. Clin Pharmacol Ther 89:400–407 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The study's main limits were small sample size and short duration.

“The main limits of our research were the small sample size and the short duration of the study.”

Probably not a substantial claim: may not pass S4 (based).

Reduced use of medication implies reduced effect of headache pain on quality of life.

“A reduced use of medication implies a reduced effect of headache pain on the quality of life.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Nabilone is a synthetic cannabinoid CB1-receptor agonist, well-tolerated and with a good safety profile.

“Nabilone is a synthetic cannabinoid CB1-receptor agonist (licensed in Canada since 1981 for chemotherapy-induced vomiting and nausea); it is well-tolerated and has a good safety profile [22, 23].”

• cites [22] Fabre LF, McLendon D (1981) The efficacy and safety of nabilone (a synthetic cannabinoid) in the treatment of anxiety. J Clin Pharmacol 21:377S–382S sourceNot checked yet

  Not checked in the free run.

• cites [23] Williamson EM, Evans FJ (2000) Cannabinoids in clinical practice. Drugs 60:1303–1314 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Randomization and allocation were carried out by an independent pharmacy through a central computer system.

“Randomization and allocation (ratio 1:1) were carried out by an independent pharmacy through a central computer system.”

• Also stated in: § Study design · plain

  “The pairs of containers were consecutively numbered for each subject according to the randomization schedule, generated by a computer.”

Classified as probably not a substantial claim.

Diagnosis was formulated according to ICHD-II criteria for medication overuse headache.

“The diagnosis was formulated according to the ICHD-II criteria for MOH [27].”

• cites [27] Olesen J, Steiner T, Bousser MG et al (2009) Proposals for new standardized general diagnostic criteria for the secondary headaches. Cephalalgia 29:1331–1336 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Nabilone is beneficial for patients with medication overuse headache, primarily reducing pain intensity and analgesic intake, and is more efficacious than ibuprofen.

“To conclude, nabilone, a cannabinoid 1-receptor agonist, at daily doses, would appear beneficial for patients suffering from MOH, primarily in reducing the intensity of pain and the analgesic intake and appeared to be significantly more efficacious than ibuprofen.”

• Also stated in: § Conclusions · plain

  “nabilone, a synthetic oral cannabinoid, is efficacious in the treatment of medication overuse headache.”

Probably not a substantial claim: may not pass S2 (checkable).

The use of nabilone would appear reasonable in the treatment of medication overuse headache for which central mechanisms are hypothesised.

“The use of nabilone, a cannabinoid1-receptor agonist, would therefore appear reasonable in the treatment of MOH for which central mechanisms are hypothesised in the maintenance of chronic head pain due to medication overuse.”

• AssumptionThe authors state this as an assumption: Medication overuse headache is caused by alterations in the nociceptive threshold and central sensitisation in susceptible individuals.

Classified as probably not a substantial claim. May combine two claims.

Cannabinoids have proven safety and modest efficacy in treatment of neuropathic pain, with some evidence in fibromyalgia and rheumatoid arthritis.

“In one recent review of published studies on non-cancer pain, cannabinoids appeared to have proven safety and modest efficacy in the treatment of neuropathic pain whereas, there are some evidences of efficacy also in fibromyalgia and rheumatoid arthritis [19].”

• cites [19] Lynch ME, Campbell F (2011) Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol 72:735–744 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Nabilone's ability to reduce DAI in both single-drug and multi-drug overusers, associated with reduction in LDQ, suggests nabilone could affect degree of dependence in both conditions.

“Nabilone’s ability to reduce DAI in both types of overusers (SDO and MDO) associated with a reduction in the LDQ score suggests that nabilone could affect the degree of dependence in both of these conditions.”

Probably not a substantial claim: may not pass S4 (based).

The results were obtained in a selected chronic headache population considered representative of the most severe medication overuse headache patients who failed all available pharmacological treatments.

“However, our results were obtained in a selected chronic headache population considered a representative sample of the most severe MOH patients who failed to respond to all available pharmacological treatments.”

Classified as probably not a substantial claim. May combine two claims.

The study was randomized, double-blind, active-controlled, crossover with allocation ratio 1:1.

“A not-for-profit, independent, randomized, double-blind, active-controlled, crossover study (using a two period design, allocation ratio 1:1) was conducted on 30 outpatients attending the University of Modena’s Interdepartmental Centre for Research on Headache and Drug Abuse (Italy), where study visits took place, clinical data were collected and drugs were dispensed.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Twenty-six subjects completed the study; four dropped out after randomization.

“Twenty-six subjects completed the study and four dropped out after randomization and allocation.”

May combine two claims.

Nabilone appears safe and well-tolerated in patients with medication overuse headache.

“This drug also appears to be safe and well-tolerated.”

• Also stated in: § Conclusions · hedged

  “Nabilone would also appear to be safe.”

Probably not a substantial claim: may not pass S4 (based).

There is no evidence on the most efficacious way to discontinue medication overuse.

“There is no evidence on the most efficacious way to discontinue medication overuse.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study protocol was approved by the Independent Ethics Committee of Modena and conducted in compliance with the Declaration of Helsinki and Good Clinical Practice.

“The study protocol was approved by the Independent Ethics Committee of Modena. The study was conducted in compliance with the provisions set forth in the Declaration of Helsinki (last version) and EU standards of Good Clinical Practice.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All patients gave written informed consent.

“All patients gave their written informed consent.”

Classified as probably not a substantial claim.

Increasing evidence is available concerning benefits of cannabinoid agents in pain management.

“Increasing evidences are available concerning the benefits of cannabinoid agents in pain management, it should prompt to design larger and longer-term studies on their effects in homogeneous populations with chronic pain [18].”

• cites [18] Aggarwal SK (2012) Cannabinergic Pain Medicine: A Concise Clinical Primer and Survey of Randomized-controlled Trial Results. Clin J Pain. (Epub 23 Feb). doi: 10.1097/AJP.0b013e31824c5e4c sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Four patients dropped out after randomization; two due to side effects (one nabilone, one ibuprofen) and two spontaneously.

“Twenty-six subjects completed the study and four dropped out after randomization and allocation. In two cases patients stopped the treatment due to the side effects of the medication (one for nabilone and one for ibuprofen). Other two subjects interrupted the study spontaneously: one subject simply changed his mind after completing the initial washout period, without starting the trial treatment (”

Classified as probably not a substantial claim.

Nabilone and ibuprofen were prepared as identical white capsules by an independent pharmacy.

“Sixty doses of nabilone (0.5 mg) and 60 doses of ibuprofen (400 mg) were prepared for each patient by an independent pharmacy, as identical white capsules and randomized in two containers, named Drug A and Drug B.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Reports of nabilone abuse are extremely rare and it has been suggested as a potential treatment for marijuana addiction.

“Reports of its abuse are extremely rare and the drug has been even recently suggested to be a potential treatment for marijuana addiction [24, 25].”

• cites [24] Ware MA, St Arnaud-Trempe E (2010) The abuse potential of the synthetic cannabinoid nabilone. Addiction 105:494–503 sourceNot checked yet

  Not checked in the free run.

• cites [25] Bedi G, Cooper ZD, Haney M (2012) Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers. Addict Biol (Epub 19 Jan). doi: 10.1111/j.1369-1600.2011.00427.x sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In these patients, the main unresolved problem is excessive use of drugs for acute treatment and overall deterioration in quality of life, so headache symptoms should be considered as part of the issue as a whole.

“In these patients, the main unresolved problem is the excessive use of drugs for the acute treatment and the overall deterioration experienced in their quality of life, so the headache symptoms should be considered as part of the issue as a whole [2, 6, 7].”

• cites [2] Meng ID, Dodick D, Ossipov MH, Porreca F (2011) Pathophysiology of medication overuse headache: insights and hypotheses from preclinical studies. Cephalalgia 31:851–860 sourceNot checked yet

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• cites [6] Diener HC, Limmroth V (2004) Medication-overuse headache: a worldwide problem. Lancet Neurol 3:475–483 sourceNot checked yet

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• cites [7] Lantéri-Minet M, Duru G, Mudge M, Cottrell S (2011) Quality of life impairment, disability and economic burden associated with chronic daily headache, focusing on chronic migraine with or without medication overuse: a systematic review. Cephalalgia 31:837–850 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Other studies gave similar results in neuropathic pain: nabilone versus gabapentin and nabilone versus dihydrocodeine.

“Other studies gave similar results in the management of neuropathic pain: one comparing nabilone and gabapentin used as add-on or mono-therapy in patients with peripheral neuropathy [20] and another comparing nabilone with dihydrocodeine in neuropathic pain [21].”

• cites [20] Bestard JA, Toth CC (2011) An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. Pain Pract 11:353–368 sourceNot checked yet

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• cites [21] Frank B, Serpell MG, Hughes J et al (2008) Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ 336:199–201 sourceNot checked yet

  Not checked in the free run.