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Journal of Pain Research 2018:11 1761–1767
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ORIGINAL RESEARCH
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/JPR.S166617
Cannabinoids and spinal cord stimulation for
the treatment of failed back surgery syndrome
refractory pain
Epifanio Mondello¹
Domenico Quattrone²
Luigi Cardia¹
Giuseppe Bova²
Raffaella Mallamace¹
Alessia A Barbagallo²
Cristina Mondello³
Carmen Mannucci³
Martina Di Pietro3
Vincenzo Arcoraci4
Gioacchino Calapai3
1Anesthesia, Intensive Care and
Pain Therapy, Azienda Ospedaliera
Universitaria “G Martino” Messina –
University of Messina, Messina, Italy;
2Pain Therapy Unit, San Vincenzo
Hospital, Azienda Sanitaria Provinciale
Messina, Messina, Italy; 3Department
of Biomedical and Dental Sciences
and Morphofunctional Imaging,
University of Messina, Messina,
Italy; 4Department of Clinical and
Experimental Medicine, University of
Messina, Messina, Italy
Objective: This study aimed to evaluate pain and its symptoms in patients with failed back
surgery syndrome (FBSS) refractory to other therapies, treated with a combination of delta-
9-tetrahydrocannabinol (THC) and cannabidiol (CBD), in association with spinal cord stimula-
tion (SCS).
Settings: Outpatients referred at Pain Unit of San Vincenzo Hospital in Taormina (Italy),
between September 2014 and January 2016.
Subjects: Eleven FBSS patients diagnosed with neuropathic pain using the Douleur
Neuropathique 4 questionnaire and suffering from moderate to severe chronic refractory
pain, and undergoing treatment with SCS and a combination of THC/CBD for 12 consecu-
tive months.
Materials and methods: All the included patients discontinued previous unsuccessful therapy
at least 2 months before the beginning of the cannabinoid therapy, with the exception of the SCS
that was continued. Patients received a fixed dosage of cannabinoid agonists (THC/CBD) that
could be increased subjective to pain control response. A Brief Pain Inventory questionnaire
was administered to measure pain and its interference with characteristic dimensions of feelings
and functions. The duration of treatment with SCS and THC/CBD combination was 12 months.
Results: Effective pain management as compared to baseline result was achieved in all the
cases studied. The positive effect of cannabinoid agonists on refractory pain was maintained
during the entire duration of treatment with minimal dosage titration. Pain perception, evaluated
through numeric rating scale, decreased from a baseline mean value of 8.18±1.07–4.72±0.9 by
the end of the study duration (12 months) (P<0.001).
Conclusion: The results indicate that cannabinoid agonists (THC/CBD) can have remarkable
analgesic capabilities, as adjuvant of SCS, for the treatment of chronic refractory pain of FBSS
patients.
Keywords: cannabinoids, delta-9-tetrahydrocannabinol, THC, cannabidiol, CBD, failed back
surgery syndrome, FBSS, refractory pain, spinal cord stimulation, SCS, cannabis
Introduction
Failed back surgery syndrome (FBSS) is defined by the International Association for
the Study of Pain as “a spinal pain of unknown origin either persisting despite surgical
intervention or appearing after surgical intervention for spinal pain originally in the
same topographical location”.1 Several conditions have been identified as underlying
causes for FBSS, such as epidural fibrosis, global or lateral canal stenosis, foraminal
stenosis, retained disc fragment, recurrent disc herniation or degeneration, spinal
instability, facet joint pain, sacroiliac joint pain, discitis, adhesive arachnoiditis, and
Correspondence: Gioacchino Calapai
Department of Biomedical and Dental
Sciences and Morphofunctional Imaging,
University of Messina, Via Consolare
Valeria 5, 98125 Messina, Italy
Tel +39 090 221 3646
Email gcalapai@unime.it
Journal name: Journal of Pain Research
Article Designation: ORIGINAL RESEARCH
Year: 2018
Volume: 11
Running head verso: Mondello et al
Running head recto: Cannabinoids and SCS for the treatment of FBSS refractory pain
DOI: http://dx.doi.org/10.2147/JPR.S166617
This article was published in the following Dove Press journal:
Journal of Pain Research
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Mondello et al
others.2 The percentage of the insurgency of chronic pain
after spinal surgery varies significantly ranging from 5% to
74.6%, and the percentage of the need for re-operation is
between 13.4% and 35%.3 Up to 20%–40% of patients who
have undergone lumbar spine surgery experience FBSS.4
Nowadays, this syndrome affects ~0.02%–2% of the general
population.5 The FBSS patients frequently suffer from mod-
erate to severe chronic pain, associated with sensory and/or
motor deficits, as well as other severe chronic pain syndromes
associated with the persistence of low back pain, deteriora-
tion or recurrence of radiculopathy, and sphincter dysfunc-
tion.6,7 The current therapeutic strategies for FBSS include
antidepressant medications, antiepileptic medications,8 deep
brain stimulation, spinal cord stimulation (SCS),9,10 epidural
and intrathecal injections,11,12 spine surgery,13 counseling,14
and exercise therapy.15 FBSS is considered an intractable
syndrome when various combinations of the existing thera-
peutic strategies prove ineffective. Opioids and their major
adjuvants usually produce positive results in the treatment of
chronic pain, especially when other therapeutic approaches
fail. There is an increasing demand for alternative therapeutic
strategies by patients and clinicians when available therapies
are marginally effective, or not well tolerated. In this con-
text, the authors assessed the effectiveness of an alternative
approach for chronic refractory pain associated with FBSS,
using cannabinoids as a multimodal treatment approach to
neuropathic pain. The plant Cannabis sativa L. has been used
for centuries, both for recreational and medicinal purposes.
Only in recent times, studies about exogenous cannabinoids
have been performed to evaluate their therapeutic value
and to investigate the role of endogenous cannabinoids
(endocannabinoids) in physiology and pathophysiology of
many neurologic and neuropsychiatric diseases.16–18 Several
types of insults which can damage the peripheral or central
somatosensory nervous system, including FBSS, can cause
neuropathic pain. It is estimated that 7%–8% of the popula-
tion in developed nations is suffering from neuropathic pain.19
To date, therapeutic options for neuropathic pain induced by
FBSS achieve effective analgesia in only less than 50% of
the cases.20 This pain could, however, be effectively treated
by drugs modulating endocannabinoid system.21 This system
is highly expressed in neurons and immune cells, and it plays
a crucial role in the development of neuropathic pain.22 This
pilot study aimed to evaluate the effect of a combination of
delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) in
FBSS refractory to other available therapeutic strategies,
including opioids, adjuvant drugs, radio frequency neuro-
modulating treatments, and SCS alone. The SCS, a treatment
modality for chronic pain that has been in use since 1967,9 is
an expensive therapy and careful selection for its suitability
is recommended. Remarkable technological advances over
the years have resulted in electrodes transitioning from
single to multi-contact arrays and stimulators from external
radiofrequency coupled to implantable rechargeable devices.
Current implantable SCS electrodes can be inserted per-
cutaneously through a Tuohy needle using essentially the
same technique as that used for an epidural catheter.23 In
this context, a retrospective study documenting the results
obtained with oral administration of cannabinoids agonists,
namely a combination of THC/CBD, in eleven refractory
FBSS patients is presented.
Materials and methods
This article reports a retrospective study, performed at Pain
Therapy Unit of San Vincenzo Hospital of Taormina, in col-
laboration with the Anesthesiology and Pain Therapy Unit
and the Department of Biomedical and Dental Sciences and
Morphofunctional Imaging of the University Hospital “G.
Martino” of Messina. All outpatients included in the study
were referred at the Pain Unit of San Vincenzo Hospital, dur-
ing the period between September 2014 and January 2016.
Treatments were performed in accordance with rules and
ethical standards on human experimentation and the Decla-
ration of Helsinki of 1964 (further revised in 2013). All the
study participants gave written informed consent (including
information on possible risks and side effects) for participa-
tion in the research study. Every precaution was taken to
protect the privacy of patients. The retrospective study was
approved by the Local Ethics Committee (Comitato Etico
Interaziendale della Provincia di Messina) with protocol
number 61/17, and the clinical study is registered with the
number NCT03210766 (www.clinicaltrials.org). Between
November 2014 and December 2015, authors included the
clinical records of eleven FBSS patients suffering from
moderate to severe chronic pain not responsive to other treat-
ment regimens (including neuromodulating techniques), and
considered eligible according to the inclusion and exclusion
criteria established for the study. The patients, aged between
49 and 77 years (median age 61.18±10.26 years), were
equally distributed (six males and five females) (Table 1).
Primary inclusion criteria in this study were the diagnosis of
FBSS refractory to other standard treatments. Patients who
had not discontinued their previous oral analgesic therapy,
at least 2 months before the beginning of the treatment with
cannabinoid agonists, were excluded. The SCS therapy,
unsatisfactory in terms of pain perception as observed from
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Cannabinoids and SCS for the treatment of FBSS refractory pain
baseline numeric rating scale (NRS) values, was not discon-
tinued (Table 1). Cannabinoid agonists (THC/CBD) were
administered in association with SCS for a treatment period
of 12 consecutive months.
The neuropathic pain was assessed using the Douleur
Neuropathique 4 (DN4) questionnaire in all the cases studied.
The DN4 questionnaire consists of a total of ten items, of
which seven items are related to the characteristics of pain
(burning, painful cold, electric shocks) and its association
with abnormal sensations (tingling, pins and needles, numb-
ness, itching), and three items are related to neurological
examination in the painful area (touch hyperesthesia, pinprick
hyperesthesia, tactile allodynia). The value of 1 was given to
each positive item, and 0 value to each negative item. The
total score was calculated as the sum of all ten items and
the cutoff value for the diagnosis of neuropathic pain was
established as a total score of 4/10.24 Basal DN4 scores of
patients ranged from 7/10 to 10/10 (mean =8.9±1.37). The
Brief Pain Inventory (BPI) allows patients to rate and refer the
severity of their pain and the degree by which pain interferes
with common dimensions of feelings and functions. The BPI
was performed by all the patients both at the first visit and at
the end of treatment (after 12 months). Initially developed
to assess pain related to cancer, the BPI has shown to be
an appropriate measure of pain caused by a wide range of
clinical conditions. The BPI is a eleven-item questionnaire
that consists of four 0–10 NRS items asking patients to rate
their pain at its “worst in the last 24 hours”, “least in the
last 24 hours”, “average”, and “actually”, with 0 indicating
“no pain” and 10 representing “pain as bad as you could
imagine”. The remaining seven BPI items probe the degree
to which pain interferes with general activity, mood, walking
ability, normal work, relations with other people, sleep, and
enjoyment of life, again using a 0–10 value scale. For these
interference items, 0 (zero) represents “does not interfere”
and 10 indicates “interferes completely”.25 Baseline NRS
Table 1 Characteristics of patients, DN4 score, and BPI’s NRS
score before (baseline) and after (nal) treatment with THC/
CBD combination for 12 consecutive months
Patient’s characteristics and questionnaires
Sex (M/F) 6/5
Age range (years) 49–77
Median age (years) 61.18±10.26
DN4 score 8.90±1.37
BPI baseline NRS score (no therapy, only SCS) 8.15±0.98
BPI nal NRS score (SCS and cannabinoid agonists) 4.72±0.9a
Note: aP<0.0001 vs BPI baseline NRS score. Data presented as mean ± SD unless
otherwise indicated.
Abbreviations: DN4, Douleur Neuropathique 4; BPI, Brief Pain Inventory; NRS,
numeric rating scale; SCS, spinal cord stimulation; THC, delta-9-tetrahydrocannabinol;
CBD, cannabidiol.
scores for average pain at visit ranged from 7 to 10 (mean
=8.15±0.98) (Table 1). Patients were visited weekly in the
first month and every 2 weeks for the entire study duration.
All patients received an oleic suspension of THC (19%) and
CBD (<1%), 25 mg/day for oral administration. The dosage
of cannabinoid agonists could be increased, depending on
the positive response to pain control.
Statistical analysis
The numerical data were expressed as the mean ± standard
deviation (SD). For each numerical parameter for basal
observation and after treatment, we separately performed
statistical comparison using the Mann–Whitney test. For
each numerical parameter, considered separately for basal
and final values, we performed a comparison between basal
observation and after treatment to evaluate the existence of
a statistically significant difference using the Wilcoxon test.
Results
In FBSS patients treated with the THC/CBD combination,
an analgesic effect was achieved in four cases within the
first month of treatment. The effect of cannabinoid ago-
nists on refractory pain was maintained during the entire
observation time with minimal dosage titration. The mean
pain perception calculated using the NRS decreased from
8.18±1.07 at first visit to 4.72±0.9 at the end of the obser-
vational time in all cases (Table 2), thus indicating marked
analgesia with the treatment. The THC/CBD combination
significantly reduced burning sensation and paresthesia
linked to FBSS. The BPI interference examination showed
that all the patients reported improvement in the quality of
sleep (11/11; P<0.01). Additionally, THC/CBD combination
enhanced mood as indicated by the rise in baseline mean
level of 5.54±0.52–3.63±0.5 by the end of the study period
Table 2 Brief Pain Inventory in failed back surgery syndrome
(FBSS) among eleven patients treated with spinal cord stimulation
alone, before (baseline) and after (nal) 12 months, and treatment
with THC/CBD, (N=11).
Brief Pain Inventory items Baseline
values
Final
values
Statistics
General activities 6.72±0.90 3.63±0.67 P<0.001
Mood 5.54±0.52 3.63±0.50 P<0.001
Walking abilities 6.45±0.82 3.27±0.78 P<0.001
Normal work 5.90±0.94 3.27±0.46 P<0.001
Relations with other people 6.09±1.04 3.09±0.94 P<0.001
Sleep 6.09±1.44 3.90±1.30 P<0.01
Enjoyment of life 6.18±0.87 3.54±1.03 P<0.001
Note: Data shown as mean ± SD.
Abbreviations: THC, delta-9-tetrahydrocannabinol; CBD, cannabidiol.
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Mondello et al
(P<0.001). Remarkably, similar results were obtained with
every item on the questionnaire.
The maximum THC/CBD combination dose prescribed
for all patients was 100 mg/day, while the minimum was 50
mg/day, with a mean dose of 68.5 mg/day. All adverse events
were transient lasting from 30 minutes to a few hours, and
not requiring medical care or suspension of therapy (Table 3).
There were no reports of any severe adverse events.
Discussion
FBSS is a symptomatological syndrome, influenced by physi-
cal, psychological, and psychosocial factors that contribute
to worsening individual quality of life. The pathological
mechanism of intractable pain related to FBSS is complex
and includes permanent inflammatory, neuropathic, and
compressive processes, and in some cases are not suscep-
tible to medical or surgical resolution.26 Treatment for this
category of patients aims to achieve relief from pain and
consequently improve quality of life and daily activities.
The diagnosis of FBSS through clinical history or history
of spine operation is not always easy. Physicians should
find the underlying causes of the pain and the mechanisms
responsible for its maintenance and enforcement. Only an
accurate diagnosis can potentially lead to the implementation
of appropriate pain management strategies; this is particu-
larly true for neuropathic pain (of radicular, ganglion, or
spine origin) which is initiated by nervous system lesions
or dysfunction and can be maintained by several different
mechanisms. Moreover, neuropathic pain is more likely to
be caused either by surgical treatment or associated diseases
(comorbidity) and is more difficult to treat than nociceptive
pain.4 Successful treatment outcomes are difficult to achieve
for chronic pain which can, in the long run, adversely affect
the patient, health care services, and eventually the society.
Although SCS can successfully induce analgesia initially,
this has been observed to be relatively temporary, with the
analgesia usually wearing out after 12–24 months,9 as in
the presented study. In this scenario, the quick onset and
prolonged analgesic effects obtained with cannabis-derived
products seem to be independent of the effect of prior SCS
therapy. From the results obtained, the superior analgesia
combined with the low incidence of adverse events suggests
that cannabis-derived products may be a valuable therapeutic
option for chronic refractory pain associated with FBSS, in
comparison to other drug classes including opioids. Canna-
bis-derived products have been used historically for chronic
pain, and are attracting renewed pharmaceutical interest for
analgesia. Epidemiological studies show that 10%–15% of
patients suffering from chronic pain use cannabis to improve
pain, sleep, and mood.18 Cannabinoid compounds mediate
their pharmacological actions by binding to the cannabinoid
receptors, namely cannabinoid type 1 receptor CB1 and can-
nabinoid type 2 receptor CB2. The CB1 receptors are located
predominantly in the nervous system, while CB2 receptors
are present in the immune cells.17 Moreover, several authors
have described cannabinoid neurophysiological system as
distinct but functionally similar to the opioid pain modulation
system.27 Recent clinical trials, investigating the effects of
the newest formulations of synthetic and naturally derived
cannabinoids, demonstrated their analgesic properties for
refractory neurogenic pain, brachial plexus injuries, and
chronic neuropathic pain.16 These studies suggest that the
administration of cannabinoid agonists should be considered
in patients suffering from chronic moderate to severe pain,
especially when other less invasive treatments and opioid
therapies fail, or when extreme adverse events are reported.28
The plant genus Cannabis contains a complex mixture of phy-
tochemicals (over 60 compounds) known as cannabinoids.
Among the cannabinoids, the most investigated are the two
major active chemical constituents, namely THC and CBD.
Cannabinoids are mixed polyketides derived biosynthetically
from malonyl-CoA and hexanoyl-CoA units prenylated with
geranyl phosphate.29 THC is the main psychoactive type of
cannabinoid, whereas CBD is the major component of canna-
bis with a distinct pharmacological and psychotropic profile
to THC. CBD (C21H30O2) is a resorcinol-based compound
devoid of the psychoactive effects of THC and, on the con-
trary, is believed to be able to attenuate the psychotomimetic
effects induced by high dosages of THC. Selective CB2 ago-
nists may reduce central effects, but these are not clinically
available. The mechanism of action of CBD is complex and
Table 3 Adverse events related to treatments
Adverse events Cases (N)
Drowsiness 4
Attention/concentration disorders 3
Dry mouth 2
Headache 2
Nausea/vomiting 2
Apathy 1
Puffy lips 1
Palpitations 1
Dizziness 1
Subjective sense of facial dysmorphism 1
Mood disorders 1
Forgetfulness 1
Increased urinary retention 1
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Cannabinoids and SCS for the treatment of FBSS refractory pain
not fully known since this molecule is a “multifaceted-target”
drug interacting with several non-endocannabinoid systems
such as receptors, ion channels, enzymes, and transport-
ers.30 CBD modulates the activity of many cellular effectors,
including the receptors CB1 and CB2,31 GPR55,32 5HT1A,33
μ- and δ-opioid,34 peroxisome proliferator-activated receptor
gamma (PPARγ),35 the transient receptor potential subfamily
V member 1 (TRPV1) cation channels,36 and fatty acid amide
hydrolase (FAAH).37
In Italy and other European countries, only a single
product consisting of a THC/CBD oromucosal spray has
been authorized by the regulatory agency for the treatment of
multiple sclerosis spasticity. However, other cannabis flower
preparations may be prescribed for patients suffering from
chronic pain conditions, refractory to conventional therapy.
In the present study, orally administered oleic suspension of
THC (19%) and CBD (<1%) was chosen chiefly because the
pharmacokinetic data indicate that intake of “high content”
of THC cannabis oil results in detectable plasma concentra-
tions of THC as compared to ingestion of “low content”
of THC cannabis oil or “mid-content” THC oil-containing
capsules.38 Additionally, the availability of the product and
the simplicity offered by the oral route of administration for
the oil suspension, in comparison to vaporization, were favor-
able factors in choosing this formulation. Due to the lack of
precise information on efficacy and safety of the product, the
study protocol involved an initial low dosage to be increased
according to the patient response.
In the cases described in the present study, the analysis
of results confirms the positive effects of treatment with
THC/CBD in patients with refractory FBSS pain. More-
over, results from BPI examination show an improvement
in mood and general activities as well (P<0.001). Overall,
THC/CBD combination was well tolerated and not asso-
ciated with any severe side effects. However, the small
number of cases and the lack of a control group are limit-
ing factors for this study to assess a definitive effect and/
or for the identification of patient population for which
treatment with THC/CBD may be appropriate. The posi-
tive effect of THC on the quality of sleep, reported in our
study, has already been observed by other authors,39 and
could perhaps positively influence pain perception. To
the best of our knowledge, this is the first study report-
ing the beneficial effects of a combination of THC/CBD
in FBSS refractory pain. Preliminary studies on cannabis
and sleep suggest that CBD may have therapeutic effects
on insomnia. Similar effects favoring sleep were observed
with THC; however, contradictory findings revealed that
this compound decreases sleep latency and could impair
sleep quality in the long term.40 As a consequence, in our
opinion, the effects of THC on pain may be independent
of an effect on sleep. Finally, cannabis-derived products
should be used cautiously in patients with a history of, or
current anxiety or panic disorder, as well as for those with
potential for reported dependence or abuse. Additionally,
careful monitoring is advised for patients with depression
and other psychiatric disorders.41
Conclusion
This is the first study that underlines the beneficial effects of
cannabinoids for the treatment of FBSS. The results suggest
that THC/CBD combination may represent an innovative
and valid strategy to treat disabling symptoms represented
by pain, nausea, and sleep disorders in FBSS patients. Fur-
thermore, in these patients, cannabinoid treatment could
positively contribute to an improved quality of life. Though
cannabinoids can have common side effects such as dry
mouth and drowsiness, the side effects profile of THC/CBD
combination seems to be milder and well tolerated. The chief
limiting factors of this study are the small number of cases of
FBSS patients with intractable refractory pain and the lack
of a control group, even though it is a general opinion that
interpretation of results obtained with placebo-controlled
trials may encounter difficulties because of the psychoactive
effects of cannabis. Additionally, it must be noted that ethical
rules in Italy are very restrictive, especially in the context
of pain treatment.
Albeit the limitations, in all the cases reported, the
beneficial effect obtained with cannabinoids in association
with SCS demonstrate that SCS therapy alone may be not
sufficient to provide adequate analgesia.
Finally, we believe that prospective clinical studies are
required to assess the real safety and efficacy of THC/CBD
combination for chronic FBSS refractory pain. In conclu-
sion, the current study suggest that THC/CBD combination
represents an alternative treatment strategy in FBSS patients
with chronic and severe pain, refractory to neuromodulating
techniques, and is a valuable adjuvant to SCS.
Acknowledgment
Authors presented an earlier version of the abstract as a poster
at the 38th Italian Society of Pharmacology (SIF) National
Meeting in Rimini (Italy) in October 2017, prior to the actual
completion or publication of the work.
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Mondello et al
Author contributions
All authors made substantial contributions to conception and
design, acquisition of data, or analysis and interpretation of
data; took part in drafting the article or revising it critically
for important intellectual content; gave final approval of the
version to be published; and agree to be accountable for all
aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
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