Comparison between Cannabis Flos and Cannabis FM2 effects on Chronic Neuropatic Pain - Pathos

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Comparison between Cannabis Flos and Cannabis FM2 effects on Chronic Neuropatic Pain

Studio osservazionale sugli effetti di Cannabis Flos e Cannabis FM2
nel dolore cronico neuropatico
Clinical Report
Pathos 2018; 25; 1. Online 2018, Mar 13
____________________________________________________
Paolo Poli,1 Cristiana Salvadori,2 Chiara Sannino 3
 1Surgeon Specialist in Anesthesia and Intensive Care and Pain Therapy
2Surgeon Specialist in Emergency Medicine
3Psychologist
Poli Pain Clinic, Pisa, Italy
Summary Cannabis based drugs are often prescribed in order to obtain pain relief and muscle relaxation: for this purpose are prescribed Cannabis based drugs with balanced ratio between Cannabis Flos (THC 6% and CBD 8%) or Italian Cannabis FM2 (THC 5-8% and CBD 7-12).
The aim of this study is to assess if there are significative differences between Cannabis Flos (THC 6% and CBD 8%) and Cannabis FM2 (THC 5-8% and CBD 7-12) effects on chronic neuropathic pain. Variables compared were pain intensity (VAS), frequence of side effects, frequence in the use of traditional analgesic drugs; Psychopatological dimensions were evaluated with Hospital Anxiety and Depression Scale (HADS). Our study suggest a better effect of Cannabis FM2 treatment, not on pain intensity but only on qualitative aspects associated to pain experience, as use of traditional analgesic drugs, frequence of side effects  and psychological conditions. Further studies are needed to confirm our conclusions.
Riassunto La prescrizione di cannabis terapeutica mediante l’olandese Cannabis Flos (THC 6% e CBD 8%) e l’italiana Cannabis FM2 (THC 5-8% and CBD 7-12%) per contrastare il dolore è oggi molto diffusa, in quanto il rapporto tra Cannabidiolo (CBD) e Delta-9-tetrahydrocannabinolo (THC) assicura un effetto equilibrato tanto a livello nervoso che muscolare: lo scopo di questo studio osservazionale è valutare se vi siano delle differenze negli effetti di Cannabis Flos (THC 6% and CBD 8%)  e di Cannabis FM2 sul dolore cronico neuropatico.
I risultati dimostrano che, di fronte a un effetto similare dei due farmaci sulla riduzione dell’intensità del dolore nel corso del tempo, aspetto quantitativo, il trattamento con FM2 si dimostra maggiormente efficace per quanto riguarda le dimensioni qualitative associate all’esperienza del dolore; nel trattamento con Cannabis FM2 si registra una minor presenza  di effetti collaterali, minor frequenza d’assunzione del tradizionale analgesico e una maggior riduzione della sintomatologia ansiosa e depressiva.
Key words Cannabis Flos, Cannabis FM2; chronic neuropathic pain; anxiety and depression symptoms linked to pain experience
Parole chiave Cannabis Flos, Cannabis FM2; dolore cronico neuropatico; sintomi ansiosi e depressivi associati al dolore

Introduction
The long journey of Medical Cannabis in Italy begins in 1998 when the Italian State approves and regulates the prescription of Cannabis based preparations for therapeutic use (Di Bella law:1 these preparations were not considered drugs and their composition varied according to the needs of patients, so there was no standardization.
Only in 2007 delta-9-tetrahydrocannabinol and dronabinol are included in a official list of drugs (Tabella dei Medicinali, section B) by Ministry of Health and in 2013 are also included Cannabis based vegetable substances.2
Thanks to these laws since 2007 it has been possible to import from Holland. This drugs, based on Cannabis sativa, can be administered orally (e.g through infusions in olive oil) or inhalation and have different THC and CBD concentrations: Cannabis Flos contains 6,5% THC and 8% CBD.
The use of these drugs has been documented in many clinical conditions, expecially in treating chronic pain. According to recent review pain management is the the main reason  for requesting and using Cannabis, a needed by 45-80% of patients using Cannabis based drugs alone or for 39 percent of patients using it as an adjunct to traditional opioid therapy.3-7
The Italian law of 2015 has authorized the use of Cannabis to improve analgesic effects not only for neuropathic pain but also for all chronic pain conditions “when other available medications have proven to be ineffective or inadeguate to the therapeutic need for patients”.8
An important change in the use of Medical Cannabis in Italy it was, due to agreement between Ministry of Health and Ministry of Defense, the beginning of italian production of Cannabis and  its availaibility, since February of 2017, of Cannabis FM2.9,10
Cannabis FM2 is based drug product by Military Chemical Pharmaceutical Factory, in Florence, according to the Good Manufacturing Practices (GMP).11 It is constituted by feminine inflorescences not fertilized of Cannabis plant,dried and planted in ground with 5-8% of THC and 7,5-12% of CBD.
The birth of Cannabis FM2 represent an important change not only for the patients but also for the italian economy:  the production within the country should ensure a greater availability and lower cost, although, during last months, there have been issues which have not provided a sufficient supplying.
Moreover, Cannabis FM2 allows to reduce importation costs and it is the first attempt, in Europe, to adopt an industrial approach in this field even though under the control and supervision of Italian Agency of Drug (AIFA).

Cannabis in Chronic Neuropatic Pain: Cannabis Flos and Cannabis FM2
Recently several meta-analysis and systematic reviews tried to make the point on the efficacy of Cannabis in chronic pain, showing that there was at least moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain; Pain syndromes with a positive response to cannabinergic therapies include chronic neuropathic pain for some kind cancer pain, spasticity, acute pain and chronic pain conditions. A recent review of National Academies of Sciences, Engineering and Medicine assess the evidence for the effectiveness of Cannabis in chronic pain, but the strength of these results are low and limited to neuropathic pain.12-22
Moreover data often comes from research and studies which employs different concentrations of THC and CBD making difficult to compare results obtained.23
Cannabis Flos and Cannabis FM2 shows a more balanced ratio between the two main components.
It has been suggested that the presence of Cannabidiol (CBD) ameliorates the psycho-active effects of delta-9-tetrahydrocannabinol (THC): CBD blocks the methabolism  of THC to 11-hydroxt-THC, more psicho-active than THC and may produces dysphoria.24-25
The aim of this study is to assess if there are significative differences on pain relief, on side effects , on use of traditional analgesic drugs and on psychological aspects between two different groups of subjects with chronic neuropathic pain, one treated with Cannabis Flos and the other one with Cannabis FM2.26

Materials and Methods
At the Poli Pain Clinic we recruited, after their informed consent, 108 subjects affected by various form of chronic pain: according to pain therapist they have received a different Cannabis based drug prescription, in particular Cannabis Flos and Cannabis FM2.
Cannabis Flos Group (n. 58) and Cannabis FM2 Group (n. 59) were evaluated at baseline, 3 months and 6 months follow up: the variables investigated at every evaluation are divided into clinical and psychological variables.
Clinical variables are pain intensity (VAS), side effects, use of traditional analgesic drug; psychological Variables are anxiety and depression symptoms measured with Hospital Anxiety and Depression Scale (HADS).27
Procedures were in accordance with the ethical standards of the responsible committe on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

The inclusion criteria for eligible patients were:
1) 18 years of age or older;
2) chronic pain for at least 3 months;
3) lack or inadequate response to conventional treatments or presence of adverse effects defined as deemed intolerable effects by patients, who refused to continue the therapy.
The exclusion criteria were:
1) pregnant or breast-feeding patients;
2) patients with severe ischemic heart disease or arhythmia;
3) patients with severe psychiatric or personality disorders, a history of cannabis or other psychoactive substances abuse or dependence.

Cannabis was administered orally, through infusions in olive oil: the prescription for the pharmacy, responsible of preparation, was 1 gram of Medical Cannabis every 10 gram of olive oil.
At the first visit, the patients were asked to sign an informed consent form, wherein they were provided informations related to therapeutic cannabis (explanation of the drug, therapeutic informations, possible acute and long term side effects, mode of consumption, effects on driving and possible interaction with other drugs). The patients were also instructed by the medical staff regarding the assumption, suggesting sublingual intake in order to speed up metabolism of Cannabis compounds.
During six months of evaluation, most patients continued to take their traditional analgesic therapy in addition to Cannabis therapy.
To evaluate the survey variables we used different tools in order to obtain a quantitative measurement of clinical and psychological dimension:

* Pain intensity
During the first examination, using the visual-analogic scale (VAS),   the patients were asked to choose their pain level from “no pain” (0 value) to “worst conceivable pain” (10 value).

* Depression and anxiety symptoms: The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale developed to detect states of depression, anxiety and emotional distress among patients affected by organic pathologies, discriminating between psychopatological and somatic symptoms. It is composed by a fourteen items: seven of them relate to anxiety and seven  relate to depression.26-27
All measurement (VAS, HADS), performed at the Baseline, were repeated, with telephone interviews, 3 months and 6 months after the onset of therapy and were used as outcome measures.

Statistical methods
Data were analysed using the SPSS software (version 23.0.1)
Trends of Pain Intensity in each group was evaluated with paired Sample T test
Comparison between Bediol and FM2 groups about Pain intensity and HADS scores at Baseline, 3 and 6 months follow up were conducted with Independent Sample T Test.
Chi-square test was used to assess the presence of relationship between Cannabis treatment and frequence of analgesic use; Chi-Square test was used also to evaluate link between Cannabis treatment and side effects frequence.
Statistical significance was at 5%

Results
Our sample was composed by 116 subjects divided into Cannabis Flos group (n. 57) and Cannabis FM2 group (n. 59) according their clinical prescriptions (Table 1).
Bediol group was composed by 43 women and 14 men, mean age 49 ± 13, affected by fibromyalgia (54%), arthritis (8%), headache (7%)and various forms of neuropathic pain (28%).
FM2 group was composed by 51 women and 8 men, mean age 53 ± 15, affected by fibromyalgia (64%), arthritis (5%), headache (10%) and various form of neuropathic pain (19%) (Figure 1a) (Figure 1b).
There were no statistically significant differences between Bediol group and FM2 group in any demographic (age and sex) and clinical variables (diseases distribution).
After completing data collection, we have verify the presence or not of  statistically differences between two groups regarding Pain intensity at Baseline, 3 month follow up, 6 month follow up (Figure 2).
In order to have a measurement of Bediol/FM2 effects on VAS scores we have calculated three kind of DVAS, for both groups, obtained by the difference between VAS Baseline and VAS three months follow up (?VAS BL), difference between VAS three months follow up and VAS six months follow up (DVAS 3), difference between VAS Baseline and VAS six months follow up (DVAS 6).
Test T for independent sample revealed no statistically differences between ?VAS BL of Bediol and FM2 (t (116)= -1,1; p>0,05), between DVAS 3 (t (116) = 0,99; p>0,05) and between DVAS 6 (t (116) = 0,6 p>0,05).
Data suggests that effects of Cannabis Flos and Cannabis FM2 on pain intensity are not different over time (Table 2).
Another important data that indirectly could suggest the lack of differences between two groups is represented by the presence of same mechanisms: indeed, in each group, paired sample T test highlights that the reduction of pain intensity is significant only compared to baseline, suggesting that pain not change in the period between 3 and 6 months, as indicated in table 2
This similar trend could indicate that both Cannabis Flos and Cannabis FM2, as Cannabis based drugs, leads to a significant reduction of pain intensity which then stabilize itself over time.
The association between kind of Cannabis treatment and frequence of sides effects was evaluated with X square test: for each step (baseline, 3 month follow up, 6 month follow up) was examined the presence of statistically relationship between time, independent variable, and frequence of side effects, considered dependent variable.
These analyzes was conducted both in Cannabis Flos group and Cannabis FM2 group.
Results demonstrated only a statistically significant relationship at 6 month follow up (X2  = 5,78; p< 0,05) so, in FM2 group registered adverse effects are less frequent than in Bediol group (Table 3) (Figure 3).
Another important examined association was the link between kind of treatment and frequency of analgesic use: the analysis process is the same to that reported above.
Also in this case, results demonstrated  only a statistically significant relationship at 6 months follow up (X2  6,24; p<0,05)showing a less using of analgesics drugs in FM2 group than in Bediol group (Table 4) (Figure 4).
Regarding Psychological dimensions, variables examined were DHADS and in particular: DHADS ANX, for both groups, obtained by the difference between HADS Anxiety scores at Baseline and HADS Anxiety scores at three months follow up (DHADS ANX BL), difference between HADS Anxiety scores three months follow up and HADS Anxiety scores six months follow up (DHADS ANX 3), difference between HADS Anxiety scores Baseline and  HADS Anxiety scores six months follow up (DHADS ANX 6).
DHADS DEP (DHADS DEP BL, DHADS DEP 3 DHADS DEP 6) and DHADS TOT (DHADS DEP BL, DHADS DEP 3 DHADS DEP 6) were calculated with the same process reported above.
Data analysis demonstrated that a DHADS ANX 6 and DHADS DEP 6 in FM2 group  were greater in a statistically significant way, than in Bediol group (t 2,27; p< 0,05; t 3,53: p<0,05), so in Cannabis FM2 group was registered a greater reduction of anxiety and depression symptoms compared to baseline than in Cannabis Flos group, at 6 month follow up (Table 5).

Discussion
Literature about Medical Cannabis use in neuropathic pain confirm the presence of effectiveness evidence, although with low strength, by Cannabis preparations with standardized ratio THC-CBD.22
This result also emerged from our study: indeed, during six months of evaluation, in both groups there is a reduction of pain intensity although it is significant only in the first three months.
Further analyses are necessary in order to investigate better the significance in pain reduction limited to three months: effects of size and lack of homogeneity of sample or demonstration of stabilizing effects? Recent  review asses the difficult to give an answer to this question due to small studies and limited follow up over time.28
Regarding the comparison between Cannabis Flos and Cannabis FM2 is it important to underline that the aim of this study is not to assess the effectiveness of a Cannabis based drug compared to another one, but verify only the presence of differences between Cannabis Flos and Cannabis FM2, in a observational perspective.
In Cannabis FM2 group we observed a better effect on chronic neuropathic pain represented by a less frequence of traditional analgesic drug use, although results not demonstrate a greater significant reduction in pain intensity, compared to Cannabis Flos group.
However, in Cannabis Flos group the frequence use of analgesic drugs , the frequence of side effects was significant greater than data registered in Cannabis FM2 group.
So it is possible speculate that if from a quantitative point of view there are no differences on chronic neuropathic pain, differences are present from a qualitative point of view: although the same variance in pain reduction, subjects in Cannabis FM2 group tolerate less side effects and they need less to make use of traditional analgesic drug.
Regarding psychological variables it possible to applying the same reasoning: one the one hand no significant differences in pain intensity reduction, on the other a significant greater reduction of anxiety and depression symptoms in Cannabis FM2 group compared to Cannabis Flos group.
Based on this data also psychological aspects could  represent a qualitative dimension linked to pain experience that registered a greater improvement in Cannabis FM2 group.

Conclusion
Our study suggest better qualitative conditions associated to pain reduction in Cannabis FM2 treatment compared to Cannabis Flos treatment after six months of evaluation.
Further studies are needed to confirm our conclusions and to carry out more detailed investigations regarding relations between variables analyzed and regarding reasons for which we have recorded these observations.

Conflitto di interessi
The authors certify the study and the publication were conducted without conflicts of interest.
Published
13th March 2018
Correspondence
sanninochiara2@gmail.com
References
9) Gazzetta Ufficiale. (2014, September 18). Tratto il giorno November 22, 2017 da Official Italian Governement Site: http://www.salute.gov.it/imgs/C_17_notizie_1737_ listaFile_itemName_0_file.pdf
25) Morgan DR ed. Therapeutic Uses of Cannabis. London: Harwood Academic, 1997.
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