Effect of adding medical cannabis to analgesic treatment
in patients with low back pain related to fibromyalgia:
an observational cross-over single centre study
M. Yassin1, A. Oron2, D. Robinson1
Department of Orthopaedics, Hasharon
Hospital, Rabin Medical Centre affiliatedwith Tel Aviv University Sackler Schoolof Medicine, Petah Tikwa;
2
Department of Orthopaedic Surgery,
Kaplan Medical Center, Affiliated with
the Hebrew University, Jerusalem, Israel.
Mustafa Yassin, MD
Amir Oron, MD
Dror Robinson, MD, PhD
Please address correspondence to:Dror Robinson, MD PhD,
Orthopaedic Research Unit,
Department of Orthopaedics,
Hasharon Hospital,
7 Keren Kayemet Str.,
Petah Tikwa, Israel.
E-mail: dror61@protonmail.com
Received on September 21, 2017; accepted
in revised form on January 23, 2018.
Clin Exp Rheumatol 2019; 37 (Suppl. 116):
S13-S20.
© Copyright Clinical andExperimental Rheumatology 2019.
1

Key words: fibromyalgia, low backpain, cannabis

Competing interests: none declared.

Clinical and Experimental Rheumatology 2019

ABSTRACT
Objective. Low back pain (LBP) occurs in many patients with fibromyalgia (FM). The current study aimed toassess the possible pain and function
amelioration associated with medicalcannabis therapy (MCT) in this setting.
Methods. 31 patients were involvedin an observational cross-over study.
The patients were screened, treatedwith 3 months of standardised analgesic therapy (SAT): 5 mg of oxycodonehydrochloride equivalent to 4.5 mg
oxycodone and 2.5 mg naloxone hydrochloride twice a day and duloxetine 30
mg once a day. Following 3 months ofthis therapy, the patients could opt for
MCT and were treated for a minimumof 6 months. Patient reported outcomes(PRO’s) included: FIQR, VAS, ODI
and SF-12 and lumbar range of motion(ROM) was recorded using the modified Schober test.
Results. While SAT led to minor improvement as compared with baseline
status, the addition of MCT allowed asignificantly higher improvement in all
PRO’s at 3 months after initiation of
MCT and the improvement was maintained at 6 months. ROM improved after 3 months of MCT and continued to
improve at 6 months.
Conclusion. This observational crossover study demonstrates an advantage of MCT in FM patients with LBP
as compared with SAT. Further randomised clinical trial studies should
assess whether these results can be generalised to the FM population at large.
Introduction
Fibromylagia (FM) is a rather common musculoskeletal affliction. A highproportion of patients are affected by
low back pain (LBP) (1). This is not
surprising as LBP affects 60%-80% of
individuals at some point in their lives,and about 10% of cases are related toFM (2). Treatment of chronic LBP isoften multi-modality and not very successful. The results of treatment in patients with LBP in the setting of FM are
better in primary FM than in secondaryFM (2). Duloxetine has been recently
demonstrated to be effective in chronic
musculoskeletal pain conditions (3).
The drug has previously been demonstrated to be effective for pain management in FM and LBP (4).
Duloxetine treatment could be associated with improvements in both pain
relief and in quality of life in Japanese patients with FM (5-7). FM isquite resistant to pharmacologic treatment, perhaps due to mitochondrial
dysfunction underlying the disease(5). A significant mitochondrial dysfunction with reduced mitochondrial
chain activities and bioenergetic levels and increased levels of oxidative
stress explains its effects on function and patient well-being additional
therapies are needed. Medical cannabis
therapy (MCT) has recently been usedin chronic LBP patients with quite remarkable functional improvement (8).
A recent meta-analysis has concluded
that most randomised clinical trials of
cannabinoids demonstrate that in fifteen of the eighteen trials that met theinclusion criteria demonstrated a significant analgesic effect of cannabinoid
as compared with placebo without serious adverse effects (9). Adverse effects
most commonly reported were generally well tolerated, mild to moderate
in severity and led to withdrawal fromthe studies in only a few cases. Previous survey of 1300 patients indicatesthat MCT is more effective than duloxetine in treating fibromyalgia, with
60 percent of respondents describing
duloxetine as ineffective (10). Endocannabinoid deficiency has been sug-

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Cannabis in fibromyalgia-associated low back pain / M. Yassin et al.

gested to lead to the ameliorative effectof MCT in fibromyalgia, a disease inwhich endocannabinoid tone appears
dysregulated. All humans possess anunderlying endocannabinoid tone thatreflects of levels of anandamide. If
endocannabinoid function were decreased, it follows that a lowered pain
threshold would be operative, alongwith derangements of digestion, mood,and sleep among the almost universal
physiological systems sub served by
the endocannabinoid system (11, 12).
In order, to evaluate the possible roleof medical cannabis therapy (MCT)in the management of LBP in FM, across-over add-on design of a trial was
performed. This design was chosen toincrease patients’ safety. Thus, no pharmaceutical treatment was stopped but
rather the MCT was added on top ofcurrent pharmacotherapy.
Methods
DesignDue to national regulations, a treatment
trial of 12 months using analgesics isrequired prior to initiation of MCT fora pain-related indication. To ensure adequacy of analgesic treatment prior to
MCT initiation, our clinic mandates a
3-month trial with analgesics prior toconsideration of MCT. This policy allows a comparison of the symptom
response of the patient cohort treatedat our clinic comparing standardised
analgesic therapy to MCT. The standardised treatment protocol in our clinic
involves duloxetine 30 mg once daily
and an opiate delivered twice to threetimes daily (most commonly Targin(oxycodone hydrochloride 5 mg andnaloxone hydrochloride anhydrous 2.5mg) as it has less gastrointestinal effects than other opiates.
This study was an observational crossover trial with participants treated for3 months by duloxetine and opiates asneeded to control their pain. Following a minimum of a 3-month therapy,
license to treat with MCT was grantedby the Israeli Ministry of Health. The
patients could continue the pharmacotherapy used so far and 20 grams of
MCT were administered by inhalationof smoke, for 6 months. The study wasapproved by the hospital ethical comS-14

mittee and registered at ClinicalTrials.gov (NCT03138460). All patientssigned a consent form for the cannabis
therapy as mandated by national law.
ParticipantsParticipants who met the inclusion
criteria were recruited from an orthopaedic pain clinic. One of the authors(DR) conducted a thorough physicalexamination that included neurologicaltesting, postural assessment, joint mobility, strength, etc.
The inclusion criteria were:
1. symptomatic LBP of more than 12
months, duration between T12 andthe gluteal fold.
2. History of symptomatic FM for atleast 12 months.
3. Failure of opiate therapy of at least
12 months.
Exclusion criteria included:
1. A self-reported history of malignancy.
2. Improvement in pain to less that 4
VAS after opiate therapy.
3. Refusal to undergo medication by
dulexotine and opiates.
4. Inability to sign an informed consent
form allowing the data to be used forresearch purposes.
5. Severe cardiovascular disease preventing MCT administration according to a cardiologist
6. Severe psychiatric disease preventing MCT administration according
to a psychiatrist
All subjects signed a consent form
permitting the use of their data for research purposes, and confidentiality
was assured using an anonymous coding system.
Participants were not asked to refrainfrom receiving other forms of therapy
and analgesics during the study.
Medical cannabis therapy
MCT therapy is legally obtained fromone of several producers following approval by the ministry of health. The
approval process requires a minimum
period of 12 months of opiate analgesic
therapy as well as a definitive findingon imaging studies indicating an organic pathology underlying the LBP. This
demand is compulsory at a national
level. Even though pathological studies
on imaging are extremely common, it

is difficult to ascertain the true clinicalrelevance of these findings, as the findings on magnetic resonance scans are
not found to be predictive of the development or duration of low-back pain
(13, 14). At least one third of sciatica
patients have asymptomatic herniations of the contralateral side (which is
asymptomatic) (15) (Table I). All patients were assessed by a spine surgeon
prior to study inclusion and a surgicaloption was ruled out. All patients considered for treatment of LBP in FM by
MCT received a minimum of 12-month
period of pharmacotherapy from arheumatologist. As the pharmacotherapy details varied, a period of standardised analgesic therapy (SAT) was
administered. Specifically, all patientsin the trial received at least 3 months ofduloxetine 30 mg once daily and Targin
5/2.5 mg twice a day (each tablet contains 5 mg of oxycodone hydrochloride
equivalent to 4.5 mg oxycodone and2.5 mg naloxone hydrochloride as 2.73
mg of naloxone hydrochloride dihydrate equivalent to 2.25 mg naloxone).
This medication is less likely thanother opiates to cause constipation andgastrointestinal side effects (16, 17).
During this 3-month period, all otheropiates and atypical analgesics were
stopped. Following the 3-month treatment, patients applied to receive permit for MCT (response time was up to
45 days) and were crossed-over to the
MCT arm (however, concomitant SAT
therapy was allowed). Patients were
evaluated prior to standardised analgesic therapy, after 3 months of SAT andafter 3 months and 6 months of MCT.
The MCT recommended was 1:4 THC
to CBD. The THC levels were less than
5%. The dose of MCT was 20 grams
per month for 3 months, administered
via smoking or vaporisation. After 3
months, according to the patient’s request and detailed usage table documenting the daily time and amount ofdrug use, an option to increase the dosage to 30 grams per month was offered.
Outcomes measures
Outcomes measures included the VAS
pain scale to evaluate measure current
pain intensity (0 to 10 scale with 10 defined as strongest pain imaginable), OsClinical and Experimental Rheumatology 2019

Cannabis in fibromyalgia-associated low back pain / M. Yassin et al.
Table I. Baseline characteristics of patientswith chronic LBP in FM.
Parametern = 31
Mean SDAge (y)Onset since first episode (y)BMI
FIQR score
VAS
Modified Schober Test (cm)
Oswestry Disability Index (ODI)

33.4 ± 12.3
4.6 ± 3.5
29.4 ± 8.5*
46.3 ± 11.1
8.1 ± 1.3
3.7 ± 1.7
77.5 ± 10.8

Fig. 1. Flow chartdetailing the study.

Advanced Imaging Findings**(more than one diagnosis is possible per patient)
Disc herniation
13/31 patients
Spondylolisthesis
0/31 patients
Degenerative changes
21/31 patients
BMI: body mass index; cm: centimetres; FIQR:
The Revised Fibromyalgia Impact Questionnaire; LBP: Low back pain; SD: Standard Deviation; VAS: Visual Analogue Scale; y: years.
*Obesity is very common in our clinic population**Advanced imaging studies included 22 patientswith computerised tomography scans, 6 patientswith magnetic resonance findings, and the rest
had both examinations.

westry Disability Index (ODI) to assess
functional limitation due to spine disorder (0–100 scale, 0 no disability, 100
total disability) and the revised Fibromyalgia Impact Questionnaire (FIQR)(0–100 scale, 0 total disability, 100 nodisability) as well as the seven-rank
Patient’s Global Impression Of Change(PGIC) Scale (reflects a patient’s belief
about the efficacy of treatment). PGIC
is a 7-point scale depicting a patient’s
rating of overall improvement. Patients rate their change as “very much
improved,” “much improved,” “minimally improved,” “no change,” “minimally worse,” “much worse,” or “verymuch worse.” (18). This was reported
as numerical values as follows:
1 very much worse
2 much worse
3 minimally worse
4 no change
5 minimally improved
6 much improved
7 very much improved
All these outcome tools are consideredvalid and reliable quantitative questionnaires to measure the magnitude ofclinical change. Physical examination
measure that was used for outcome assessment was the modified-modified
Schober test to assess lumbar flexion(19, 20).
Clinical and Experimental Rheumatology 2019

Table II. Means and standard deviations of disability, pain intensity and Schober test at
various time-points.
Parameter

Screening(-3 months)

Baseline(Time 0)MCT
(3 months)

MCT(6 months)

p value
ANOVA

VAS
FIQR
ODI
Schober Test (cm)8.1 ± 1.2
46.3 ± 1177.5 ± 10.6
3.7 ± 1.7

8.1 ± 1.4
45.3 ± 10.2
73.7 ± 11.4
3.5 ± 1.8

5.3 ± 1.3
68.7 ± 15.6
45.9 ± 19.1
4.2 ± 2.2

3.3 ± 2.2
80.5 ± 12.2
30.7 ± 13.6
5.3 ± 1.5

p<.0001
p<.0001
p<.0001
p<.0001

ANOVA: analysis of variance; cm: centimeters; FIQR: The Revised Fibromyalgia Impact Questionnaire; ODI: Oswestry Disability Index; VAS: Visual Analogue Scale.

Other endpoints assessed
Analgesic drug use was assessed according to the patients’ medical records, including the list of pharmacy
dispensed medications. The use of
medication following SAT was gradedas 1-need for increased doses, 2- continued dosage required during MCT,
3- decrease by less than one half of
medication consumption, 4-decrease by
more than one half, 5-no other analgesics consumed.
Study procedure
All participants had SAT drug therapy.
Following cross-over SAT could continue and MCT was administered. The patients were examined by one of the authors (DR) every 3 months. The amountof medications dispensed was recorded
and the patients filled out the outcome
measures. Physical examination was
carried out by one of the authors (DR).

Statistical analysis
All analyses were performed using theAnalyse-it add-on of the for-Microsoft
Excel software program. ANOVA wasused to compare the outcome scoresat various timepoints. After assessing the normal distribution of thedata, separate univariate analyses ofcovariance with time as the covariate
were performed to determine whether
there were significant differences between the treatment groups scores offunctional disability, pain and lumbar
ROM. A Tukey-Kramer approach wasused to maintain the alpha level at
p<0.05. This test compares the meansof all pairs of groups.
It controls the error rate simultaneously
for all k(k+1)/2 contrasts. Differenceswith p-values ≤0.05 were considered
statistically significant. Continuous
variables were summarised as means
and standard deviations. The change in
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Cannabis in fibromyalgia-associated low back pain / M. Yassin et al.

Fig. 2. Histograms of PGIC distribution comparing SAT response with MCT response at different
timepoints.

ODI, VAS and Schober test from BL to
6 months was compared according to
the presence or absence of degenerative changes and disc herniation using
the Student’s t-test.

Results
Thirty-one patients with chronic LBP in
the setting of FM (28 women, 3 men)
aged between 21-75 years participatedin the study. Per national regulations,a year-long therapy of analgesics isrequired to allow receiving MCT treatment. To make sure that conventional
therapy could not alleviate sufficiently
their symptom burden, the patientswere administered SAT for at least 3
months. 3 patients dropped out and therest received the MCT arm later. Patient
flow through the study is shown in the
CONSORT flow chart (Fig. 1).
Baseline characteristics of the 31 participants who completed the study are
given in Table I.
Mean values and standard deviationsof the pain intensity, FIQR, ODI andlumbar ROM scores at baseline and at
6 months are presented in Table II. As
it can be seen, the opiate treatment allowed minimal improvement in mostevaluated functional outcome measuresthough not in the PGIC (Fig. 2). The
later addition of MCT allowed a significantly greater decrease of pain concomitant with significant improvementin Schober test. The PGIC was significantly higher in the MCT time interval
than in the opiate time interval (Fig. 3
and 4, ANOVA p<0.0001).
The spine range of motion was notaffected by SAT but improved by 3months MCT (Tukey-Kramer all pairs
comparisons, Fig. 4). Interestingly the
improvement might continue during

Fig. 3. PGIC at baseline (following 3 months of opiate therapy) indicates a substantial patient impression of improvement during MCT therapy with similar
results after 3 and 6 months. The difference to the PGIC after opiate therapy is significant.

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Clinical and Experimental Rheumatology 2019

Cannabis in fibromyalgia-associated low back pain / M. Yassin et al.

therapy with better range of motion
after 6 months of MCT though the difference between modified Schober testat 3 months versus 6 months was not
significant (p>0.09).
Changes in ODI, VAS and Schober test
were independent of the presence or absence of disc herniation or degenerativechanges (Student’s t-test, p>0.1).
Medications consumption decreased
following MCT therapy. The decrease
was more marked following 6 monthsof MCT (Student’s t-test 4.5, p<0.001,
Fig. 6).
Adverse events during MCT therapy
included: red eyes in 28 of 31 patients,
increased appetite in 5 of 31 patients,and sore throat in 3 out of 31 patients.
The adverse events were mild and did
not require MCT alteration. Adverse
events during SAT therapy included
depression in 2 out of 31 patients, lossof appetite in 8 out of 31 patients, hemorrhoids in 4 out of 31 patients, constipation in 15 out of 31 patients, zombielike feeling in 5 out of 31 patients. One
patient had to be operated for hemorrhoids and in another 6 patients SAT
was stopped due to side effects.
Discussion
This study appears to indicate that supplementation of analgesic therapy withMCT alleviate pain in FM patients suffering from LBP. The study design was
an observational cross-over study of aconsecutive patient cohort. This study
design is a requirement of the current

Fig. 4. PGIC is affected by the type of therapy administered. 3 months MCT significantly enhances the PGIC as can be seen from the quartile analysis.

Clinical and Experimental Rheumatology 2019

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Cannabis in fibromyalgia-associated low back pain / M. Yassin et al.

Fig. 5. Changes in lumbar spine flexion as assessed by modified Schober test.

national legislation that allows licensingof MCT only to patient with an organic
cause of LBP, who have failed a significant treatment with pharmaceuticalanalgesics. This SAT procedure might
help to select patients who are lesslikely to have symptoms relief using
conventional medication. However, theconsort diagram describing the patient
flow indicates that most patients who
begun SAT did not have pain relief withSAT and went on to MCT. This finding
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conforms to that of a survey of 1300
patients in which duloxetine and pregabalin were only highly effective in 10
percent of patients with FM and totallyineffective in about 60 percent (10). The
pain relief as well as the PGIC was significantly higher using the MCT therapy. The symptom relief occurs even as
early as after 3 months of MCT. The
improvement in spinal ROM takes moretime and ROM was higher at 6 months
as compared with 3 months of MCT.

The cohort evaluated was too small fora meaningful subgroup analysis regarding the possibility that different imaging
diagnoses might respond differently to
MCT therapy. However, there were no
significant differences in ODI change
according to the presence or absence ofdisc herniation or degenerative changes.
The mechanism of pain relief by MCT
in FM associated LBP is not clear. One
option relates to the anti-inflammatory
effect of cannabis (21). Several subClinical and Experimental Rheumatology 2019

Cannabis in fibromyalgia-associated low back pain / M. Yassin et al.

Fig. 6. Analgetic medication consumption following MCT therapy.

stances within the inhaled cannabis
smoke possess such activity (22). Increased production of eicosanoids that
promote the resolution of inflammation
is caused by cannabidiol (22). Anotheroption is the amelioration of neuropathy by CB-2 receptor activation. A recent meta-analysis has indicated thatabout 30 percent of LBP have a neuropathic component (23).
A recent Cochrane meta-analysis has
concluded that currently, there is insufficient evidence for recommendation
for any cannabinoid preparations for
symptom management in patients withchronic pain associated with rheumatic
diseases. Unfortunately, the included
studies did not include any studies using the inhaled whole flower preparation(24). The effect of synthetic compounds
or extracts might differ from that of thewhole plant extract both due to different mechanism of entry into the bodyas well as the possible chaperone effectof the many so called minor molecules
present in the whole plant (25). The improvement observed in range of spinal
motion might be due to decreased muscle tonus. Cannabis has been known to
Clinical and Experimental Rheumatology 2019

reduce muscle spasm and rigidity (26).
In fact, Dr. Russo has suggested back in2004 that fibromyalgia among other diseases is caused by clinical deficiency of
endocannabinoids (27, 28). Subsequent
research has supported this concept. The
degree of improvement observed following MCT appears higher than thatobserved using duloxetine in FM (29).
Prior studies employing synthetic cannabinoids have shown that tolerability of
FM patients to nabilone is low (30). The
tolerability of MCT in our study was highand no patients had to stop the therapy
due to adverse events. The majority ofpatients elected during MCT to decreaseor discontinue pharmaceutical analgesic
consumption. Prior research has shownthat cannabis has an opiate sparing effectin analgesia (31). In view of the current
opioid dependence epidemic, the usageof treatments that might reduce opiate
consumption is of interest.
The disadvantages of the current study
include the lack of standardisation of
the amount of THC\CBD consumed.
This deficiency prevents the assessmentof a possible dose-response curve in
MCT. As FM patients are currently in-eligible for MCT therapy, only a small
sub-class of FM patients (those withmajor LBP symptoms) was included.
Further research is needed to compare
the results of FM patients without LBP
to those with LBP. Prior studies haveindicated that approximately 40 percent
of patients with FM suffer from chronic
LBP (32).
The advantages of the current study arethat it is the first one to describe resultsin LBP treatment in the setting of FM.
The results appear to indicate improvement in both subjective patient assessed
questionnaires as well as spinal rangeof motion. The decrease in opiate consumption is also an advantage of the
MCT therapy. The cross-over design
reduces the treatment variability as theresults are paired. However, as the patients are aware that limited pain alleviation will allow access to MCT therapy,
a potential bias of the SAT arm occurs.
This might bias the study results andsuch bias could only be eliminated by
the comparison of a placebo controlledgroup to the results of MCT therapy.
This bias is a cause of concern and afuture RCT should be performed.
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Cannabis in fibromyalgia-associated low back pain / M. Yassin et al.

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