Cbd Oil Stroke Shop – Sandy Beach Hotel Cbd Drops For Pain cbd oil stroke Sandy Beach Hotel power cbd oil reviews Denver Cbd Oil. Lu Chengjun said bitterly. It s all my fault. How does Hao Add multiple health benefits to your favorite meals with just a few drops of Plant Power CBD oil, designed for foodies. Cannabinoids in the management of difficult to treat pain This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as
Cbd Oil Stroke Shop – Sandy Beach Hotel
Cbd Drops For Pain cbd oil stroke Sandy Beach Hotel power cbd oil reviews Denver Cbd Oil.
Lu Chengjun said bitterly. It s all my fault.
How does Hao Ren want to cooperate After all, everyone is in the same Cbd Oil Co2 Extraction cbd oil stroke industry.
One step. Wei Lan also looked at Hao Ren, cbd oil stroke it is difficult for ordinary people to open a store in Yanjing, but if Hao Ren wants to do cbd gummies 1050 mg it, he probably doesn t need to pay for it himself, and countless people are willing to give Hao the money.
He is not short of money, but it is absolutely impossible to be slaughtered how to use hemp oil for back pain by others.
Just like Lina, cbd oil stroke if he sold his former how many times a day to use cbd oil boss directly, the company would close down immediately.
Provide a place to educate the children Colorado Cbd Oil Online cbd oil stroke of their nearby villages.
Not far away, Daniel, who was sitting quietly in cbd oil stroke front of a separate table, heard Hao Yue s voice, turned his head, saw that cbd oil stroke it How To Use Cbd Oil For Pain power cbd oil reviews was her, got up and quickly came to his side.
While talking, Hong Xun s secretary walked in from the outside and handed Hong How To Use Cbd Oil For Pain power cbd oil reviews Xun a quotation.
When he returned, Hao Ren cbd oil stroke Zebra Cbd Oil saw several people standing on the edge power cbd oil reviews Lord Jones Cbd Oil Review of his land, as if they were waiting for someone.
Have you eaten yet We made something casual today, and I ll go and warm it up for you.
2 also took a day off, and even the year end bonuses were given out early.
Da Niu, what s wrong Although Hao Ren looked ahead, he also saw Daniel s movements.
This, this is what our bank hemp fusion cbd gummies gave to you, Mr.
They all say that the dumplings are not cbd oil stroke as delicious as dumplings.
His body was enjoying himself, but his mind cbd oil stroke was cbd oil stroke Zebra Cbd Oil always thinking about what happened painless with cbd oil power 2500 before.
You want to sell the car to my employee Hao Ren raised his brows.
She thought for a moment and said, For the Administration Department, cbd oil stroke I recommend sending Zhao Ying over.
We are all bloggers with millions of fans. Believe it or not, a video will make you condemned by the cbd oil stroke whole network.
Only Cbd Oil Co2 Extraction cbd oil stroke when you actually eat the products from Hao Ren s shop can you really feel the sky defying effect, and cbd oil stroke How To Use Cbd Oil For Pain power cbd oil reviews even if you don t care how much you spend, you should stick to it.
Seeing Hao Ren s gentle smile, Chen Yao felt that her eyes were a little blurry.
Hao Ren also held out a hand to shake the other party s.
Backstage, the manager and assistant were all staring at the screen in front of Colorado Cbd Oil Online cbd oil stroke them, their eyes extremely excited, The cbd oil stroke heat has risen power cbd oil reviews Lord Jones Cbd Oil Review again, haha, it s not even halfway yet, the heat has almost caught up cbd oil stroke Zebra Cbd Oil with the previous peak, Jingjing is too good to find someone to sing on stage.
Hao Ren smiled and said, I cbd oil stroke ordered a hemp seed oil reddit different How To Use Cbd Oil For Pain power cbd oil reviews car to drive.
When the two of them went downstairs together, the younger sister saw that, her eyes lit up and she couldn t help but boast, Sister in law is so pretty today.
Hao Ren looked at it again and found that it was really the case, and he was relieved.
In Liuzhou City, then vesl cbd gummies security cannuka cbd healing skin balm issues are Cbd Oil Co2 Extraction cbd oil stroke guaranteed.
Oh, what s cbd oil stroke Zebra Cbd Oil the matter surprised. Ren Xiang took out a document from his bag again, handed it to why cant i find out where quicksilver cbd oil is manufactured and the address .
- hemp oil and blood thinners: It Fab Cbd Chews retains the full spectrum of compounds found in hemp, including the thc.
- good edibles that have 100mg: But Fab Cbd Chews you can also use other cbd products, such as edibles, softgels, and vape pens.
- it is what it is cap: 0Additional ingredients3. Health Plus Life Cbd
- indica strain for sleep: The most common side effects that were reported, however, were diarrhea fatigue changes in appetite sleepiness a comprehensive review of 132 studies that 100 Mg Capsule Cbd Oil took place in 2011 confirmed that not only does cbd have very few side effects, but it also doesn t have any profound negative effects on how the body functions.
Hao Ren, and said with a smile, This is an award letter cbd oil stroke to invite President Hao to become an honorary doctorate Sandy Beach Hotel cbd oil stroke in our university.
Meng Xuedong smiled, Do you know how much their salary is This is the secret of the company, where can I find out Meng Liang rolled his eyes and said speechlessly, However, Brother Hao is so rich, The staff cbd oil stroke should be treated well.
If I remember correctly, many rich people in your country are conducting longevity experiments.
Otherwise, they will sell it three or four times.
The other party even asked them to reduce it to 100, cbd gummies 50 mg per gummy which is the core product of the company.
They knew that their daughter was driving a Porsche, and the car logo was easy to recognize.
Now our various products All of them have achieved a lot of improvement.
There are myths and legends in our country. cbd oil stroke It is said that there was a bigu pill cbd oil stroke in Colorado Cbd Oil Online cbd oil stroke ancient times.
In this way, they could see Colorado Cbd Oil Online cbd oil stroke their children every day, and there was no reason cbd oil stroke to refuse.
In terms of equipment, we Huaxing Group in China say second, no cbd oil stroke one says first.
Hearing this, Hao Ren s eyes lit up, and he continued.
Well, it s not New Year s Day soon. I m here to ask you for leave with Sister Yao.
Moreover, this thing requires a lot cbd oil stroke of high precision machines, and Hao Ren also needs to be power cbd oil reviews Lord Jones Cbd Oil Review realized Colorado Cbd Oil Online cbd oil stroke through the system, not to mention millions of reputation points.
You are so embarrassed to speak. Wu Xing said dissatisfiedly.
Beauty, I see your palmistry cbd oil stroke Sandy Beach Hotel cbd oil stroke as someone from Fuhou, but your career line has been bleak lately
She used to be a model, and she still has a lot of research on cbd oil stroke cosmetics.
Wang Tiejun opened his mouth Sandy Beach Hotel cbd oil stroke and said, get a vaccination.
My mother said that this box was made by Luban s mechanical technique.
Businessmen, investing in this activity is all cbd oil stroke about getting what you need.
We don t have time to ink with you. Right now, we can either sign a contract and leave with the money, or you can find a way to pay for the medical expenses.
How is it Mr. Hao, can you still take it Meng Liang said with a smile.
Hao cbd oil stroke Ren said with a smile, How thc overconsumption long have you been waiting here, why didn t you go in Hee hee, it s not too long, just arrived.
after. Thinking of their previous salary of more than 3,000 yuan, these people are immediately filled with a sense of responsibility for this job.
The cbd oil stroke self cbd oil stroke service card charging machine is there.
We produce the products, and he Colorado Cbd Oil Online cbd oil stroke pays, one billion yuan, accounting for 30 cbd oil stroke of the shares
People like Mr. Hao are naturally not bound.
Foreign customers are also customers, let them know that they have cbd oil stroke Zebra Cbd Oil to Cbd Oil Co2 Extraction cbd oil stroke spend so much power cbd oil reviews Lord Jones Cbd Oil Review more and no one will hemp derived cbd gummies be happy.
Five percent, Director Yi, you sell a bottle of laundry detergent for 1000, we can only take 50, is it a bit too Colorado Cbd Oil Online cbd oil stroke much Director Wang frowned and looked at Cbd Oil Co2 Extraction cbd oil stroke Yi Xueming.
Yang Qi s eyes kept on cbd oil stroke tincture cbd oil near me Hao Yue and Hao Ren cbd oil brand on the stage, and she couldn t believe that this big handed senior turned out to be their roommate s brother.
There is no intrigue among colleagues in the company.
Seeing Lu Sisi on stage, Xu Jing s eyes also lit up.
Chen Yao watched them scolding, her eyes were calm, and when they had said enough, she took out a piece cbd oil distributors near me of paper cbd oil for smoking cessation from her pocket.
Hao. Is this the how much cbd isolate from a kilogram of raw cbd oil cbd oil stroke Zebra Cbd Oil full amount cbd oil stroke the room manager asked cautiously.
Hao Ren shook his head and laughed. Meng Liang gestured to the saleswoman, who free cbd sample free shipping 2022 obediently stood behind Hao Ren and cbd oil stroke gently pinched power cbd oil reviews Lord Jones Cbd Oil Review Hao Ren s shoulders.
After watching it, Bai Qiaoyan raised her head and cbd oil stroke Zebra Cbd Oil looked cbd oil stroke at the laundry detergent in front of her with a dignified expression, Where did this laundry detergent come from She is not stupid, Seeing the efficacy of this laundry detergent, she immediately saw a huge crisis.
Just when cbd oil stroke Zebra Cbd Oil he was about cbd oil cleveland to add a friend, Hao buy cbd oil in fulton ny Ren saw cbd gummies san francisco weedmaps Chen Yao s message, his eyes flashed, and he felt something was wrong.
You should have bought .
cbd oil australia pbs
a set in Yanjing for a long time.
For a thousand acres cbd oil stroke of land, Hao anxiety insomnia reddit Ren estimated that at most a hundred people would kannaway images be needed.
Boss, I think Director Yi is still too careful, and simply sells five hundred and one bottles.
Of course, because the third male role is relatively small, it is You don t have to be in cbd oil stroke Zebra Cbd Oil the crew all the time.
In Colorado Cbd Oil Online cbd oil stroke Liuzhou City, in a villa, Qu Shan looked at her daughter watching TV, sitting on the Sandy Beach Hotel cbd oil stroke balcony, Read the book leisurely.
Jenny suddenly realized, I didn t expect this.
Hao Ren learned that cbd oil stroke he Sandy Beach Hotel cbd oil stroke rushed to the Shinhwa How To Use Cbd Oil For Pain power cbd oil reviews No.
But she understands Chen Yao s choice. She is too lonely and too difficult
Mr. Hao, our cooperation
Hao Ren smiled helplessly, That was left by Xu Yujia.
Of course, the salary is also very high, with a monthly salary of at least 30,000 yuan.
Startled by Hao Ren s voice, Xiaomei, Dai Shixuan alibaba cbd oil .
is cbd oil legal for minors in washington state
and the others do cbd gummies hurt your liver turned around and looked at Hao Ren, their eyes suddenly lit up.
Chen Yao gave Hao Ren a How To Use Cbd Oil For Pain power cbd oil reviews blank look, picked up a few documents on the table, and sighed.
In cbd oil stroke addition, there is also the cbd oil stroke environment in the factory.
It is only natural for the teacher to correct the homework for the apprentice.
These steels cost another 20 million. Part of it is what Hao Ren intends to use to expand the Shinhwa No.
How much do you estimate is their bottom line Hao Ren asked.
The price was just right, cbd oil stroke several million, and it was a good deal for Hao Ren to replace it with publicity fees and no cash needed.
That s for the little sister. I ll put it aside.
The little boy looked up at Hao Ren and Xu Sheng, and asked curiously.
Although Hao Ren s scale is not big enough, at this rate of development, we will depend on cbd oil stroke each other to hemp and olive cbd oil a large extent for our financial income in the future.
Ren was in no cbd oil stroke hurry and cbd oil stroke waited quietly. Soon, Chen Yao s slightly hoarse voice sounded.
Hao Ren Nod. The third person to report is Shao Feng, the head of the personnel department.
I heard that there are a lot of artists in the remote culture, but they are Sandy Beach Hotel cbd oil stroke not very hemp based products famous.
Part of it will gradually dissipate
Mr. Yang, I m sorry, there are cbd oil stroke some entertainment outside, I didn t know you were here, sorry.
While does cbd oil take away tooth pain packing, Chen Hongbing what kind of cbd oil do the doctors recommend was Cbd Oil Co2 Extraction cbd oil stroke still cursing Cbd Oil Co2 Extraction cbd oil stroke fiercely, best sativa edibles That cbd oil stroke damn little bitch, we ll find the media as soon as we go out.
Hao Yue rolled her eyes and smiled, Brother, what are you doing Send me some money when it where can i find the strongest cbd gummies s time.
Hearing this, Chen Hongbing s expression changed.
Why, cbd oil stroke are you trying to invite me to dinner I m sure I have a hemp oil infusions meal here, but I have a project here.
Senior, you can also go with us when the time comes.
Although Hao Ren thought so in his heart, he smiled and said, This is no problem, I ll tell Lu cbd oil stroke Yuan later, you can just go cbd oil stroke directly.
Yi Xueming added. I will power cbd oil reviews Lord Jones Cbd Oil Review handle this matter.
It s lower, but if power cbd oil reviews Lord Jones Cbd Oil Review it s the same as the market cbd oil stroke price, why would he come to talk to How To Use Cbd Oil For Pain power cbd oil reviews the other party.
Hong Xun said in a deep voice. Yi Xueming glanced at it and knew that the other party was thinking of negotiating, and he was picking on this fault and picking that fault, and finally lowered the cbd oil stroke Sandy Beach Hotel cbd oil stroke price by 300,000 yuan again.
Rise up, so we will talk about this matter. However, Hao Ren smiled, power cbd oil reviews Perhaps, I do.
By the way, I will improve Sandy Beach Hotel cbd oil stroke your network. Chen Yao also thought of Zhang Jinghong.
Provide a place to cbd oil stroke educate the children of their nearby villages.
Hearing the employees of Shinhwa Company talking, the employees of Remote Culture Media were all saddened and their envious eyes cbd gummies 300mg were all red.
Although the other party is willing to provide us with where to buy hemp flower positions, it does not .
cbd v hemp oil
mean that everyone is competent.
However, seeing Hao Ren, a man stepped forward and greeted with a smile, Mr.
After the treatment was finalized, the rest was left to Shao cbd oil private label suppliers Feng.
I want to are high tech cbd gummies worth buying find the boss of the remote culture company and fight for this opportunity.
Chen Yao tidied Cbd Oil Co2 Extraction cbd oil stroke up Hao Ren s collar. Although it was almost Cbd Oil Co2 Extraction cbd oil stroke March, the weather was still relatively cold.
Could it be that Colorado Cbd Oil Online cbd oil stroke if the butcher cbd oil stroke Zhang died, he couldn t eat pigs with hair Qin An was relieved when he saw Hao Ren s words.
Zhou Feng cbd oil stroke also smiled bitterly, feeling inexplicably offended.
When the big boss of the company arrives, he will definitely be questioned.
The school cafeteria power cbd oil reviews Lord Jones Cbd Oil Review basically didn t close cbd oil stroke until after 9 00 pm.
Therefore, she also said, Nianwei, you also know that I am usually busy Sandy Beach Hotel cbd oil stroke with work.
Xu is 20mg thc a lot Jing was a little proud, I don t need you to tell me this.
Hello, sir, are you on your own or have an appointment At edibles healthy the door, a woman asked softly.
This is a typical example. Hao Ren smiled, I m cbd oil stroke not good at this, I can just say a few words at that time.
The first Xu Jing can appear in Huaxia Kingdom, then the second, third, or mood rite cbd gummies review even tenth can cbd gummies and mg appear.
Hao Ren felt that his teeth were aching. cbd oil stroke He had been fifty or sixty in thirty years.
I finally, soar Stare with your heart and don t be afraid
For Xu Jing s concert, the government arranged hundreds of police officers alone.
Jiang Guohua rolled his eyes at him, but still said, You re right.
The next Cbd Oil Co2 Extraction cbd oil stroke moment, she said softly, Husband, thank you.
Mr. Hao, I went to buy this. There are cbd oil stroke only a few of these models in the store.
However, for him, it doesn t make any sense.
Unless you know them well, but those who are familiar How To Use Cbd Oil For Pain power cbd oil reviews with Hao Ren will tell strong melatonin gummies him what the other person likes Jenny sighed, I can cbd oil stroke only find a way to use the relationship in China.
The configuration almost dazzled her. Compared with the BMWs and cbd oil products online Mercedes Benzes she has seen, I don t know how luxurious it is.
Liang Ying cbd oil stroke s face was a cbd oil crossfit little cbd oil stroke ugly, and she was despised by a dog, How To Use Cbd Oil For Pain power cbd oil reviews and cbd oil stroke Health Plus Life Cbd she couldn t Cbd Oil Co2 Extraction cbd oil stroke get angry even if she lied to her.
This is an incentive mechanism that can give Hao Ren a sense of crisis.
The employees in the cbd oil stroke building cbd oil stroke poured out of the door one after another.
The boss is How To Use Cbd Oil For Pain power cbd oil reviews worthy of being a boss. He is already so rich, yet he still works so hard
Although there are only three minutes of suggestions, Guan Le still made eight suggestions, that is, some corresponding policies.
Guo Lin also promised me to drag me into the Liuzhou Chamber of Commerce.
More importantly, this is what my boss asked for.
Xu Jing also took it generously, thanking him by the way.
Hao Ren turned around casually and nodded in satisfaction.
Hao Ren said cbd oil stroke with power cbd oil reviews a smile. It turns out that you came here because of this matter.
The Healthy Cooking Hack to Boost Your Favorite Meals
Plant Power CBD adds multiple health benefits to your favorite meals with just a few drops
If you’re a health conscious foodie, Plant Power Plant Power is a dropper-design CBD oil that can be added to food for an instant nutritional boost. Approved by the Colorado Department of Agriculture, Plant Power’s own hemp strain is cultivated to the highest level of scrutiny to ensure effectiveness in each bottle. The CBD formula is free of pesticides, and all plants used are organically grown.
Moreover, every hemp plant used undergoes pharmaceutical-grade certification under guidelines set forth by the Good Manufacturing Processes (GMP), which is monitored by the Food and Drug Administration (FDA). This additional level of attention during the manufacturing process guarantees each Plant Power purchase meets both brand and federal regulation standards.
How Can CBD Be Used in Cooking?
As the list of available CBD-based products expands across industries, it can be hard to discern effective formulas from the rest. Luckily, Plant Power is transparent on formulas and manufacturing processes, giving customers an inside look at what they’re putting in their body and how the CBD oil is made. Of the many benefits of incorporating CBD throughout your daily routine, Plant Power is different in that it’s designed to be used in cooking.
Using CBD when prepping meals is easy and does not alter the taste of your favorite food. The combination of natural oils produces a light fragrance that’s enjoyable on its own or when added to a dish. Plant Power CBD oils come in a variety of combinations that compliment traditional spices and seasonings. It’s currently available in:
- Coconut, Pineapple and Lemongrass
- Orange, Cinnamon and Ginger
- Mint, Rosemary and Lemongrass
If you’re thinking of trying CBD for yourself but are interested in alternatives to oils, consider Plant Power’s CBD gummies, which are packed with the same healthy ingredients.
Unfortunately, as is the case with many fads, there are many barriers preventing more individuals from trying CBD oil for themselves. Among many reasons, socioeconomic reign supreme as a deterrent for trying health-conscious products, which often tote a higher price tag or are only available at select retailers. Plant Power believes in the benefits of CBD oil and has set out on a mission to give back . Through every purchase of Plant Power, you’re helping those less-fortunate gain access to naturally-derived CBD oil, which can unlock many health benefits. Every month, Plant Power gifts products to those in need. If you think you’d be a fit for Plant Power’s give back program, simply send in your story to [email protected]
Shop Now: Coconut, Pineapple and Lemongrass CBD Oil 40mg, $74.99; via plantpower.io.
- Boosts mood.
- Promotes relaxation.
- Pain and inflammation management.
- Improves quality of sleep.
Shop Now: Orange, Cinnamon and Ginger CBD 40mg, $74.99; via plantpower.io.
- Boosts mood.
- Promotes relaxation.
- Pain and inflammation management.
- Improves quality of sleep.
Shop Now: Mint, Rosemary and Lemongrass CBD 40mg, $74.99; via plantpower.io.
- Reduces anxiety.
- Boosts mood.
- Promotes relaxation.
- Pain and inflammation management.
- Improves quality of sleep.
All products featured on GRAZIA are independently selected by our editors. However, when you buy something through our retail links, GRAZIA may earn an affiliate commission.
Cannabinoids in the management of difficult to treat pain
This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol ® ) and nabilone (Cesamet ® ) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC (partial CB1 receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB1 receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
Keywords: cannabinoids, tetrahydrocannabinol, cannabidiol, analgesia, pain management, multiple sclerosis
Chronic pain represents an emerging public health issue of massive proportions, particularly in view of aging populations in industrialized nations. Associated facts and figures are daunting: In Europe, chronic musculoskeletal pain of a disabling nature affects over one in four elderly people (Frondini et al 2007), while figures from Australia note that older half of older people suffer persistent pain, and up to 80% in nursing home populations (Gibson 2007). Responses to an ABC News poll in the USA indicated that 19% of adults (38 million) have chronic pain, and 6% (or 12 million) have utilized cannabis in attempts to treat it (ABC News et al 2005).
Particular difficulties face the clinician managing intractable patients afflicted with cancer-associated pain, neuropathic pain, and central pain states (eg, pain associated with multiple sclerosis) that are often inadequately treated with available opiates, antidepressants and anticonvulsant drugs. Physicians are seeking new approaches to treatment of these conditions but many remain concerned about increasing governmental scrutiny of their prescribing practices (Fishman 2006), prescription drug abuse or diversion. The entry of cannabinoid medicines to the pharmacopoeia offers a novel approach to the issue of chronic pain management, offering new hope to many, but also stoking the flames of controversy among politicians and the public alike.
This article will attempt to present information concerning cannabinoid mechanisms of analgesia, review randomized clinical trials (RCTs) of available and emerging cannabinoid agents, and address the many thorny issues that have arisen with clinical usage of herbal cannabis itself (“medical marijuana”). An effort will be made to place the issues in context and suggest rational approaches that may mitigate concerns and indicate how standardized pharmaceutical cannabinoids may offer a welcome addition to the pharmacotherapeutic armamentarium in chronic pain treatment.
Cannabinoids and analgesic mechanisms
Cannabinoids are divided into three groups. The first are naturally occurring 21-carbon terpenophenolic compounds found to date solely in plants of the Cannabis genus, currently termed phytocannabinoids (Pate 1994). The best known analgesic of these is Δ 9 -tetrahydrocannabinol (henceforth, THC)( Figure 1 ), first isolated and synthesized in 1964 (Gaoni and Mechoulam 1964). In plant preparations and whole extracts, its activity is complemented by other “minor” phytocannabinoids such as cannabidiol (CBD) ( Figure 1 ), cannabis terpenoids and flavonoids, as will be discussed subsequently.
Molecular structures of four cannabinoids employed in pain treatment.
Long before mechanisms of cannabinoid analgesia were understood, structure activity relationships were investigated and a number of synthetic cannabinoids have been developed and utilized in clinical trials, notably nabilone (Cesamet ® , Valeant Pharmaceuticals), and ajulemic acid (CT3, IP-751, Indevus Pharmaceuticals) ( Figure 1 ).
In 1988, the first cannabinoid receptor was identified (CB1) (Howlett et al 1988) and in 1993, a second was described (CB2) (Munro et al 1993). Both are 7-domain G-protein coupled receptors affecting cyclic-AMP, but CB1 is more pervasive throughout the body, with particular predilection to nociceptive areas of the central nervous system and spinal cord (Herkenham et al 1990; Hohmann et al 1999), as well as the peripheral nervous system (Fox et al 2001; Dogrul et al 2003) wherein synergy of activity between peripheral and central cannabinoid receptor function has been demonstrated (Dogrul et al 2003). CB2, while commonly reported as confined to lymphoid and immune tissues, is also proving to be an important mediator for suppressing both pain and inflammatory processes (Mackie 2006). Following the description of cannabinoid receptors, endogenous ligands for these were discovered: anandamide (arachidonylethanolamide, AEA) in 1992 in porcine brain (Devane et al 1992), and 2-arachidonylglycerol (2-AG) in 1995 in canine gut tissue (Mechoulam et al 1995) ( Figure 1 ). These endocannabinoids both act as retrograde messengers on G-protein coupled receptors, are synthesized on demand, and are especially active on glutamatergic and GABA-ergic synapses. Together, the cannabinoid receptors, their endogenous ligands (“endocannabinoids”) and metabolizing enzymes comprise the endocannabinoid system (ECS) (Di Marzo et al 1998), whose functions have been prosaically termed to be “relax, eat, sleep, forget and protect” (p. 528). The endocannabinoid system parallels and interacts at many points with the other major endogenous pain control systems: endorphin/enkephalin, vanilloid/transient receptor potential (TRPV), and inflammatory. Interestingly, our first knowledge of each pain system has derived from investigation of natural origin analgesic plants, respectively: cannabis (Cannabis sativa, C. indica) (THC, CBD and others), opium poppy (Papaver somniferun) (morphine, codeine), chile peppers (eg, Capsicum annuum, C. frutescens, C. chinense) (capsaicin) and willow bark (Salix spp.) (salicylic acid, leading to acetylsalicylic acid, or aspirin). Interestingly, THC along with AEA and 2-AG, are all partial agonists at the CB1 receptor. Notably, no endocannabinoid has ever been administered to humans, possibly due to issues of patentability and lack of commercial feasibility (Raphael Mechoulam, pers comm 2007). For an excellent comprehensive review of the endocannabinoid system, see Pacher et al (2006), while Walker and Huang have provided a key review of antinociceptive effects of cannabinoids in models of acute and persistent pain (Walker and Huang 2002).
A clinical endocannabinoid deficiency has been postulated to be operative in certain treatment-resistant conditions (Russo 2004), and has received recent support in findings that anandamide levels are reduced over controls in migraineurs (Sarchielli et al 2006), that a subset of fibromyalgia patients reported significant decreased pain after THC treatment (Schley et al 2006), and the active role of the ECS in intestinal pain and motility in irritable bowel syndrome (Massa and Monory 2006) wherein anecdotal efficacy of cannabinoid treatments have also been claimed.
The endocannabinoid system is tonically active in control of pain, as demonstrated by the ability of SR141716A (rimonabant), a CB1 antagonist, to produce hyperalgesia upon administration to mice (Richardson et al 1997). As mentioned above, the ECS is active throughout the neuraxis, including integrative functions in the periacqueductal gray (Walker et al 1999a; Walker et al 1999b), and in the ventroposterolateral nucleus of the thalamus, in which cannabinoids proved to be 10-fold more potent than morphine in wide dynamic range neurons mediating pain (Martin et al 1996). The ECS also mediates central stress-induced analgesia (Hohmann et al 2005), and is active in nociceptive spinal areas (Hohmann et al 1995; Richardson et al 1998a) including mechanisms of wind-up (Strangman and Walker 1999) and N-methyl-D-aspartate (NMDA) receptors (Richardson et al 1998b). It was recently demonstrated that cannabinoid agonists suppress the maintenance of vincristine-induced allodynia through activation of CB1 and CB2 receptors in the spinal cord (Rahn et al 2007). The ECS is also active peripherally (Richardson et al 1998c) where CB1 stimulation reduces pain, inflammation and hyperalgesia. These mechanisms were also proven to include mediation of contact dermatitis via CB1 and CB2 with benefits of THC noted systemically and locally on inflammation and itch (Karsak et al 2007). Recent experiments in mice have even suggested the paramount importance of peripheral over central CB1 receptors in nociception of pain (Agarwal et al 2007)
Cannabinoid agonists produce many effects beyond those mediated directly on receptors, including anti-inflammatory effects and interactions with various other neurotransmitter systems (previously reviewed (Russo 2006a). Briefly stated, THC effects in serotonergic systems are widespread, including its ability to decrease 5-hydroxytryptamine (5-HT) release from platelets (Volfe et al 1985), increase its cerebral production and decrease synaptosomal uptake (Spadone 1991). THC may affect many mechanisms of the trigeminovascular system in migraine (Akerman et al 2003; Akerman et al 2004; Akerman et al 2007; Russo 1998; Russo 2001). Dopaminergic blocking actions of THC (Müller-Vahl et al 1999) may also contribute to analgesic benefits.
The glutamatergic system is integral to development and maintenance of neuropathic pain, and is responsible for generating secondary and tertiary hyperalgesia in migraine and fibromyalgia via NMDA mechanisms (Nicolodi et al 1998). Thus, it is important to note that cannabinoids presynaptically inhibit glutamate release (Shen et al 1996), THC produces 30%–40% reduction in NMDA responses, and THC is a neuroprotective antioxidant (Hampson et al 1998). Additionally, cannabinoids reduce hyperalgesia via inhibition of calcitonin gene-related peptide (Richardson et al 1998a). As for Substance P mechanisms, cannabinoids block capsaicin-induced hyperalgesia (Li et al 1999), and THC will do so at sub-psychoactive doses in experimental animals (Ko and Woods 1999). Among the noteworthy interactions with opiates and the endorphin/enkephalin system, THC has been shown to stimulate beta-endorphin production (Manzanares et al 1998), may allow opiate sparing in clinical application (Cichewicz et al 1999), prevents development of tolerance to and withdrawal from opiates (Cichewicz and Welch 2003), and rekindles opiate analgesia after a prior dosage has worn off (Cichewicz and McCarthy 2003). These are all promising attributes for an adjunctive agent in treatment of clinical chronic pain states.
The anti-inflammatory contributions of THC are also extensive, including inhibition of PGE-2 synthesis (Burstein et al 1973), decreased platelet aggregation (Schaefer et al 1979), and stimulation of lipooxygenase (Fimiani et al 1999). THC has twenty times the anti-inflammatory potency of aspirin and twice that of hydrocortisone (Evans 1991), but in contrast to all nonsteroidal anti-inflammatory drugs (NSAIDs), demonstrates no cyclo-oxygenase (COX) inhibition at physiological concentrations (Stott et al 2005a).
Cannabidiol, a non-euphoriant phytocannabinoid common in certain strains, shares neuroprotective effects with THC, inhibits glutamate neurotoxicity, and displays antioxidant activity greater than ascorbic acid (vitamin C) or tocopherol (vitamin E) (Hampson et al 1998). While THC has no activity at vanilloid receptors, CBD, like AEA, is a TRPV1 agonist that inhibits fatty acid amidohydrolase (FAAH), AEA’s hydrolytic enzyme, and also weakly inhibits AEA reuptake (Bisogno et al 2001). These activities reinforce the conception of CBD as an endocannabinoid modulator, the first clinically available (Russo and Guy 2006). CBD additionally affects THC function by inhibiting first pass hepatic metabolism to the possibly more psychoactive 11-hydroxy-THC, prolonging its half-life, and reducing associated intoxication, panic, anxiety and tachycardia (Russo and Guy 2006). Additionally, CBD is able to inhibit tumor necrosis factor-alpha (TNF-α) in its own right in a rodent model of rheumatoid arthritis (Malfait et al 2000). At a time when great concern is accruing in relation to NSAIDs in relation to COX-1 inhibition (gastrointestinal ulcers and bleeding) and COX-2 inhibition (myocardial infarction and cerebrovascular accidents), CBD, like THC, inhibits neither enzyme at pharmacologically relevant doses (Stott et al 2005a). A new explanation of inflammatory and analgesic effects of CBD has recently come to light with the discovery that it is able to promote signaling of the adenosine receptor A2A by inhibiting the adenosine transporter (Carrier et al 2006).
Other “minor phytocannabinoids” in cannabis may also contribute relevant activity (McPartland and Russo 2001). Cannabichromene (CBC) is the third most prevalent cannabinoid in cannabis, and is also anti-inflammatory (Wirth et al 1980), and analgesic, if weaker than THC (Davis and Hatoum 1983). Cannabigerol (CBG) displays sub-micromolar affinity for CB1 and CB2 (Gauson et al 2007). It also exhibits GABA uptake inhibition to a greater extent than THC or CBD (Banerjee et al 1975), suggesting possible utilization as a muscle relaxant in spasticity. Furthermore, CBG has more potent analgesic, anti-erythema and lipooxygenase blocking activity than THC (Evans 1991), mechanisms that merit further investigation. It requires emphasis that drug stains of North American (ElSohly et al 2000; Mehmedic et al 2005), and European (King et al 2005) cannabis display relatively high concentrations of THC, but are virtually lacking in CBD or other phytocannabinoid content.
Cannabis terpenoids also display numerous attributes that may be germane to pain treatment (McPartland and Russo 2001). Myrcene is analgesic, and such activity, in contrast to cannabinoids, is blocked by naloxone (Rao et al 1990), suggesting an opioid-like mechanism. It also blocks inflammation via PGE-2 (Lorenzetti et al 1991). The cannabis sesquiterpenoid β-caryophyllene shows increasing promise in this regard. It is anti-inflammatory comparable to phenylbutazone via PGE-1 (Basile et al 1988), but simultaneously acts as a gastric cytoprotective (Tambe et al 1996). The analgesic attributes of β-caryophyllene are increasingly credible with the discovery that it is a selective CB2 agonist (Gertsch et al 2007), with possibly broad clinical applications. α-Pinene also inhibits PGE-1 (Gil et al 1989), while linalool displays local anesthetic effects (Re et al 2000).
Cannabis flavonoids in whole cannabis extracts may also contribute useful activity (McPartland and Russo 2001). Apigenin inhibits TNF-α (Gerritsen et al 1995), a mechanism germane to multiple sclerosis and rheumatoid arthritis. Cannflavin A, a flavone unique to cannabis, inhibits PGE-2 thirty times more potently than aspirin (Barrett et al 1986), but has not been subsequently investigated.
Finally, β-sitosterol, a phytosterol found in cannabis, reduced topical inflammation 65% and chronic edema 41% in skin models (Gomez et al 1999).
Available cannabinoid analgesic agents and those in development
Very few randomized controlled trials (RCTs) have been conducted using smoked cannabis (Campbell et al 2001) despite many anecdotal claims (Grinspoon and Bakalar 1997). One such study documented slight weight gain in HIV/AIDS subjects with no significant immunological sequelae (Abrams et al 2003). A recent brief trial of smoked cannabis (3.56% THC cigarettes 3 times daily) in HIV-associated neuropathy showed positive results on daily pain, hyperalgesia and 30% pain reduction (vs 15% in placebo) in 50 subjects over a treatment course of only 5 days (Abrams et al 2007) ( Table 1 ). This short clinical trial also demonstrated prominent adverse events associated with intoxication. In Canada, 21 subjects with chronic pain sequentially smoked single inhalations of 25 mg of cannabis (0, 2.5, 6.0, 9.5% THC) via a pipe three times a day for 5 days to assess effects on pain (Ware et al 2007) with results the authors termed “modest”: no changes were observed in acute neuropathic pain scores, and a very low number of subjects noted 30% pain relief at the end of the study ( Table 1 ). Even after political and legal considerations, it remains extremely unlikely that crude cannabis could ever be approved by the FDA as a prescription medicine as outlined in the FDA Botanical Guidance document (Food and Drug Administration 2004; Russo 2006b), due to a lack of rigorous standardization of the drug, an absence of Phase III clinical trials, and pulmonary sequelae (bronchial irritation and cough) associated with smoking (Tashkin 2005). Although cannabis vaporizers reduce potentially carcinogenic polyaromatic hydrocarbons, they have not been totally eliminated by this technology (Gieringer et al 2004; Hazekamp et al 2006).
Results RCTs of cannabinoids in treatment of pain syndromes ()
|Drug||Subject number N =||RCT indication||Trial duration||Results/Reference|
|Ajulemic Acid||21||Neuropathic pain||7 day crossover||VAS improved over placebo (p = 0.02) (Karst et al 2003)|
|Cannabis, smoked||50||HIV neuropathy||5 days||Decreased daily pain (p = 0.03) and hyperalgesia (p = 0.05), 52% with >30% pain reduction vs placebo (p = 0.04) (Abrams et al 2007)|
|Cannabis, Smoked||21||Chronic neuropathic pain||5 days||No acute benefit on pain, average daily pain lower on high THC cannabis vs placebo (p = 0.02 ) (Ware et al 2007)|
|Cannador||419||Pain due to spasm in MS||15 weeks||Improvement over placebo in subjective pain associated with spasm (p = 0.003) (Zajicek et al 2003)|
|Cannador||65||Post-herpetic neuralgia||4 weeks||No benefit observed (Ernst et al 2005)|
|Cannador||30||Post-operative pain||Single doses, daily||Decreasing pain intensity with increased dose (p = 0.01)(Holdcroft et al 2006)|
|Marinol||24||Neuropathic pain in MS||15–21 days, crossover||Median numerical pain (p = 0.02), median pain relief improved (p = 0.035) over placebo (Svendsen et al 2004)|
|Marinol||40||Post-operative pain||Single dose||No benefit observed over placebo (Buggy et al 2003)|
|Nabilone||41||Post-operative pain||3 doses in 24 hours||NSD morphine consumption. Increased pain at rest and on movement with nabilone 1 or 2 mg (Beaulieu 2006)|
|Sativex||20||Neurogenic pain||Series of 2-week N-of-1 crossover blocks||Improvement with Tetranabinex and Sativex on VAS pain vs placebo (p < 0.05), symptom control best with Sativex (p < 0.0001) (Wade et al 2003)|
|Sativex||24||Chronic intractable pain||12 weeks, series of N-of-1 crossover blocks||VAS pain improved over placebo (p < 0.001) especially in MS (p < 0.0042) (Notcutt et al 2004)|
|Sativex||48||Brachial plexus avulsion||6 weeks in 3 two-week crossover blocks||Benefits noted in Box Scale-11 pain scores with Tetranabinex (p = 0.002) and Sativex (p = 0.005) over placebo (Berman et al 2004)|
|Sativex||66||Central neuropathic pain in MS||5 weeks||NRS analgesia improved over placebo (p = 0.009) (Rog et al 2005)|
|Sativex||125||Peripheral neuropathic pain||5 weeks||Improvements in NRS pain levels (p = 0.004), dynamic allodynia (p = 0.042), and punctuate allodynia (p = 0.021) vs placebo (Nurmikko et al 2007)|
|Sativex||56||Rheumatoid arthritis||Nocturnal dosing for 5 weeks||Improvements over placebo morning pain on movement (p = 0.044), morning pain at rest (p = 0.018), DAS-28 (p = 0.002), and SF-MPQ pain at present (p = 0.016) (Blake et al 2006)|
|Sativex||117||Pain after spinal injury||10 days||NSD in NRS pain socres, but improved Brief Pain Inventory (p = 0.032), and Patients Global Impression of Change (p = 0.001) (unpublished)|
|Sativex||177||Intractable cancer pain||2 weeks||Improvements in NRS analgesia vs placebo (p = 0.0142), Tetranabinex NSD (Johnson and Potts 2005)|
|Sativex||135||Intractable lower urinary tract symptoms in MS||8 weeks||Improved bladder severity symptoms including pain over placebo (p = 0.001) (unpublished)|
Abbreviations: MS, multiple sclerosis; NRS, numerical rating scale; NSD, no signifi cant difference; RCTs, randomized clinical trials; VAS, visual analogue pain scales.
Oral dronabinol (THC) is marketed in synthetic form as Marinol ® (Solvay Pharmaceuticals) in various countries, and was approved in the USA for nausea associated with chemotherapy in 1985, and in 1992 for appetite stimulation in HIV/AIDS. Oral dronabinol’s expense, variability of action, and attendant intoxication and dysphoria have limited its adoption by clinicians (Calhoun et al 1998). Two open label studies in France of oral dronabinol for chronic neuropathic pain in 7 subjects (Clermont-Gnamien et al 2002) and 8 subjects (Attal et al 2004), respectively, failed to show significant benefit on pain or other parameters, and showed adverse event frequently requiring discontinuation with doses averaging 15–16.6 mg THC. Dronabinol did demonstrate positive results in a clinical trial of multiple sclerosis pain in two measures (Svendsen et al 2004), but negative results in post-operative pain (Buggy et al 2003) ( Table 1 ). Another uncontrolled case report in three subjects noted relief of intractable pruritus associated with cholestatic jaundice employing oral dronabinol (Neff et al 2002). Some authors have noted patient preference for whole cannabis preparations over oral THC (Joy et al 1999), and the contribution of other components beyond THC to therapeutic benefits (McPartland and Russo 2001). Inhaled THC leads to peak plasma concentration within 3–10 minutes, followed by a rapid fall while levels of intoxication are still rising, and with systemic bioavailability of 10%–35% (Grotenhermen 2004). THC absorption orally is slow and erratic with peak serum levels in 45–120 minutes or longer. Systemic bioavailability is also quite low due to rapid hepatic metabolism on first pass to 11-hydroxy-THC. A rectal suppository of THC-hemisuccinate is under investigation (Broom et al 2001), as are transdermal delivery techniques (Challapalli and Stinchcomb 2002). The terminal half-life of THC is quite prolonged due to storage in body lipids (Grotenhermen 2004).
Nabilone (Cesamet) ( Figure 1 ), is a synthetic dimethylheptyl analogue of THC (British Medical Association 1997) that displays greater potency and prolonged half-life. Serum levels peak in 1–4 hours (Lemberger et al 1982). It was also primarily developed as an anti-emetic in chemotherapy, and was recently re-approved for this indication in the USA. Prior case reports have noted analgesic effects in case reports in neuropathic pain (Notcutt et al 1997) and other pain disorders (Berlach et al 2006). Sedation and dysphoria were prominent sequelae. An RCT of nabilone in 41 post-operative subjects actually documented exacerbation of pain scores after thrice daily dosing (Beaulieu 2006) ( Table 1 ). An abstract of a study of 82 cancer patients on nabilone claimed improvement in pain levels after varying periods of follow-up compared to patients treated without this agent (Maida 2007). However, 17 subjects dropped out, and the study was neither randomized nor controlled, and therefore is not included in Table 1 .
Ajulemic acid (CT3, IP-751) ( Figure 1 ), another synthetic dimethylheptyl analogue, was employed in a Phase II RCT in 21 subjects with improvement in peripheral neuropathic pain (Karst et al 2003) ( Table 1 ). Part of its analgesic activity may relate to binding to intracellular peroxisome proliferator-activator receptor gamma (Liu et al 2003). Peak plasma concentrations have generally been attained in 1–2 hours, but with delays up to 4–5 hours is some subjects (Karst et al 2003). Debate surrounds the degree of psychoactivity associated with the drug (Dyson et al 2005). Current research is confined to the indication of interstitial cystitis.
Cannador ® (IKF-Berlin) is a cannabis extract administered in oral capsules, with differing figures as to THC:CBD ratios (reviewed in (Russo and Guy 2006)), generally approximately 2:1. Two pharmacokinetic studies on possibly related material have been reported (Nadulski et al 2005a; Nadulski et al 2005b). In a Phase III RCT employing Cannador in spasticity in multiple sclerosis (MS) (CAMS) (Zajicek et al 2003) ( Table 1 ), no improvement was noted in the Ashworth Scale, but benefit was observed in spasm-associated pain on subjective measures. Both Marinol and Cannador produced reductions in pain scores in long-term follow-up (Zajicek et al 2005). Cannador was assayed in postherpetic neuralgia in 65 subjects with no observed benefit (Ernst et al 2005) ( Table 1 ), and in 30 post-operative pain subjects (CANPOP) without opiates, with slight benefits, but prominent psychoactive sequelae (Holdcroft et al 2006) ( Table 1 ).
Sativex ® (GW Pharmaceuticals) is an oromucosal whole cannabis-based spray combining a CB1 partial agonist (THC) with a cannabinoid system modulator (CBD), minor cannabinoids and terpenoids plus ethanol and propylene glycol excipients and peppermint flavoring (McPartland and Russo 2001; Russo and Guy 2006). It was approved by Health Canada in June 2005 for prescription for central neuropathic pain in multiple sclerosis, and in August 2007, it was additionally approved for treatment of cancer pain unresponsive to optimized opioid therapy. Sativex is a highly standardized pharmaceutical product derived from two Cannabis sativa chemovars following Good Agricultural Practice (GAP) (de Meijer 2004), yielding Tetranabinex ® (predominantly-THC extract) and Nabidiolex ® (predominantly-CBD extract) in a 1:1 ratio. Each 100 μL pump-action oromucosal Sativex spray actuation provides 2.7 mg of THC and 2.5 mg of CBD. Pharmacokinetic data are available, and indicate plasma half lives of 85 minutes for THC, 130 minutes for 11-hydroxy-THC and 100 minutes for CBD (Guy and Robson 2003). Sativex effects commence in 15–40 minutes, an interval that permits symptomatic dose titration. A very favorable adverse event profile has been observed in over 2500 patient years of exposure in over 2000 experimental subjects. Patients most often ascertain an individual stable dosage within 7–10 days that provides therapeutic relief without unwanted psychotropic effects (often in the range of 8–10 sprays per day). In all RCTs, Sativex was adjunctively added to optimal drug regimens in subjects with intractable symptoms, those often termed “untreatable.” Sativex is also available by named patient prescription in the UK and the Catalonia region of Spain. An Investigational New Drug (IND) application to study Sativex in advanced clinical trials in the USA was approved by the FDA in January 2006 in patients with intractable cancer pain.
The clinical trials performed with Sativex have recently been assessed in two independent review articles (Barnes 2006; Pérez 2006). In a Phase II clinical trial in 20 patients with neurogenic symptoms (Wade et al 2003), Tetranabinex, Nabidiolex, and Sativex were tested in a double-blind RCT vs placebo ( Table 1 ). Significant improvement was seen with both Tetranabinex and Sativex on pain (especially neuropathic), but post-hoc analysis showed symptom control was best with Sativex (p < 0.0001), with less intoxication than with THC-predominant extract.
In a Phase II double-blind crossover study of intractable chronic pain (Notcutt et al 2004) in 24 subjects, visual analogue scales (VAS) were 5.9 for placebo, 5.45 for Nabidiolex, 4.63 for Tetranabinex and 4.4 for Sativex extracts (p < 0.001). Sativex produced best results for pain in MS subjects (p < 0.0042) (Table 1 ).
In a Phase III study of pain associated due to brachial plexus avulsion (N = 48) (Berman et al 2004), fairly comparable benefits were noted in Box Scale-11 pain scores with Tetranabinex and Sativex extracts ( Table 1 ).
In a controlled double-blind RCT of central neuropathic pain, 66 MS subjects showed mean Numerical Rating Scale (NRS) analgesia favoring Sativex over placebo (Rog et al 2005) ( Table 1 ).
In a Phase III double-blind, placebo-controlled trial (N = 125) of peripheral neuropathic pain with allodynia (Nurmikko et al 2007), Sativex produced highly statistically significant improvements in pain levels, dynamic and punctate allodynia ( Table 1 ).
In a SAFEX study of Phase III double-blind RCT in 160 subjects with various symptoms of MS (Wade et al 2004), 137 patients elected to continue on Sativex after the initial study (Wade et al 2006). Rapid declines were noted in the first twelve weeks in pain VAS (N = 47) with slower sustained improvements for more than one year. During that time, there was no escalation of dose indicating an absence of tolerance to the preparation. Similarly, no withdrawal effects were noted in a subset of patients who voluntarily stopped the medicine abruptly. Upon resumption, benefits resumed at the prior established dosages.
In a Phase II double-blind, randomized, placebo-controlled, 5-week study of 56 rheumatoid arthritis patients with Sativex (Blake et al 2006), employed nocturnal treatment only to a maximum of 6 sprays per evening (16.2 mg THC + 15 mg CBD). In the final treatment week, morning pain on movement, morning pain at rest, DAS-28 measure of disease activity, and SF-MPQ pain at present all favored Sativex over placebo ( Table 1 ).
Results of a Phase III study (N = 177) comparing Sativex, THC-predominant extract and placebo in intractable pain due to cancer unresponsive to opiates (Johnson and Potts 2005) demonstrated that Sativex produced highly statistically significant improvements in analgesia ( Table 1 ), while the THC-predominant extract failed to produce statistical demarcation from placebo, suggesting the presence of CBD in the Sativex preparation was crucial to attain significant pain relief.
In a study of spinal injury pain, NRS of pain were not statistically different from placebo, probably due to the short duration of the trial, but secondary endpoints were clearly positive ( Table 1 ). Finally, in an RCT of intractable lower urinary tract symptoms in MS, accompanying pain in affected patients was prominently alleviated ( Table 1 ).
Highly statistically significant improvements have been observed in sleep parameters in virtually all RCTs performed with Sativex in chronic pain conditions leading to reduced “symptomatic insomnia” due to symptom reduction rather than sedative effects (Russo et al 2007).
Common adverse events (AE) of Sativex acutely in RCTs have included complaints of bad taste, oral stinging, dry mouth, dizziness, nausea or fatigue, but do not generally necessitate discontinuation, and prove less common over time. While there have been no head-to-head comparative RCTs of Sativex with other cannabinoid agents, certain contrasts can be drawn. Sativex (Rog et al 2005) and Marinol (Svendsen et al 2004) have both been examined in treatment of central neuropathic pain in MS, with comparable results ( Table 1 ). However, adverse events were comparable or greater with Marinol than with Sativex employing THC dosages some 2.5 times higher due to the presence of accompanying CBD (Russo 2006b; Russo and Guy 2006).
Similarly, while Sativex and smoked cannabis have not been employed in the same clinical trial, comparisons of side effect profiles can be made on the basis of SAFEX studies of Sativex for over a year and up to several years in MS and other types of neuropathic pain (Russo 2006b; Wade et al 2006), and government-approved research programs employing standardized herbal cannabis from Canada for chronic pain (Lynch et al 2006) and the Netherlands for general conditions (Janse et al 2004; Gorter et al 2005) over a period of several months or more. As is evident in Figure 2 ( Figure 2 ), all adverse events are more frequently reported with herbal cannabis, except for nausea and dizziness, both early and usually transiently reported with Sativex (see (Russo 2006b) for additional discussion).
Comparison of adverse events (AE) encountered with long term therapeutic use of herbal cannabis in the Netherlands (Janse et al 2004; Gorter et al 2005) and Canada (Lynch et al 2006), vs that observed in safety-extension (SAFEX) studies of Sativex oromucosal spray (Russo 2006; Wade et al 2006).
Practical issues with cannabinoid medicines
Phytocannabinoids are lipid soluble with slow and erratic oral absorption. While cannabis users claim that the smoking of cannabis allows easy dose titration as a function of rapid onset, high serum levels in a short interval inevitably result. This quick onset is desirable for recreational purposes, wherein intoxication is the ultimate goal, but aside from paroxysmal disorders (eg, episodic trigeminal neuralgia or cluster headache attack), such rapid onset of activity is not usually necessary for therapeutic purposes in chronic pain states. As more thoroughly reviewed elsewhere (Russo 2006b), cannabis smoking produces peak levels of serum THC above 140 ng/mL (Grotenhermen 2003; Huestis et al 1992), while comparable amounts of THC in Sativex administered oromucosally remained below 2 ng/mL (Guy and Robson 2003).
The vast majority of subjects in Sativex clinical trials do not experience psychotropic effects outside of initial dose titration intervals ( Figure 2 ) and most often report subjective intoxication levels on visual analogue scales that are indistinguishable from placebo, in the single digits out of 100 (Wade et al 2006). Thus, it is now longer tenable to claim that psychoactive effects are a necessary prerequisite to symptom relief in the therapeutic setting with a standardized intermediate onset cannabis-based preparation. Intoxication has remained a persistent issue in Marinol usage (Calhoun et al 1998), in contrast.
Recent controversies have arisen in relation to non-steroidal anti-inflammatory drugs (NSAID), with concerns that COX-1 agents may provoke gastrointestinal ulceration and bleeding, and COX-2 drugs may increase incidents of myocardial infarction and cerebrovascular accidents (Fitzgerald 2004; Topol 2004). In contrast, neither THC nor CBD produce significant COX inhibition at normal dosage levels (Stott et al 2005a).
Frequent questions have been raised as to whether psychoactive drugs may be adequately blinded (masked) in randomized clinical trials. Internal review and outside analysis have confirmed that blinding in Sativex spasticity studies has been effective (Clark and Altman 2006; Wright 2005). Sativex and its placebo are prepared to appear identical in taste and color. About half of clinical trial subjects reported previous cannabis exposure, but results of two studies (Rog et al 2005; Nurmikko et al 2007) support the fact that cannabis-experienced and naïve patients were identical in observed efficacy and adverse event reporting
Great public concern attends recreational cannabis usage and risks of dependency. The addictive potential of a drug is assessed on the basis of five elements: intoxication, reinforcement, tolerance, withdrawal and dependency. Drug abuse liability (DAL) is also assessed by examining a drug’s rates of abuse and diversion. US Congress placed cannabis in Schedule I of the Controlled Substances Act in 1970, with drugs categorized as addictive, dangerous, possessing severe abuse potential and no recognized medical value. Marinol was placed in Schedule II, the category for drugs with high abuse potential and liability to produce dependency, but certain recognized medical uses, after its FDA approval in 1985. Marinol was reassigned to Schedule III in 1999, a category denoting a lesser potential for abuse or lower dependency risk after documentation that little abuse or diversion (Calhoun et al 1998) had occurred. Nabilone was placed and has remained in Schedule II since 1985.
The degree to which a drug is reinforcing is determined partly by the by the rate of its delivery to the brain (Samaha and Robinson 2005). Sativex has effect onset in 15–40 minutes, peaking in a few hours, quite a bit slower than drugs of high abuse potential. It has been claimed that inclusion of CBD diminishes psychoactive effects of THC, and may lower potential drug abuse liability of the preparation (see Russo (2006b)) for discussion). Prior studies from Sativex clinical trials do not support the presence reinforcement or euphoria as problems in administration (Wade et al 2006).
Certain facets of acute cannabinoid exposure, including tachycardia, hypothermia, orthostatic hypotension, dry mouth, ocular injection, intraocular pressure decreases, etc. are subject to rapid tachyphylaxis upon continued administration (Jones et al 1976). No dose tolerance to the therapeutic effects of Sativex has been observed in clinical trials in over 1500 patient-years of administration. Additionally, therapeutic efficacy has been sustained for several years in a wide variety of symptoms; SAFEX studies in MS and peripheral neuropathic pain, confirm that Sativex doses remain stable or even decreased after prolonged usage (Wade et al 2006), with maintenance of therapeutic benefit and even continued improvement.
Debate continues as to the existence of a clinically significant cannabis withdrawal syndrome with proponents (Budney et al 2004), and questioners (Smith 2002). While withdrawal effects have been reported in recreational cannabis smokers (Solowij et al 2002), 24 volunteers with MS who abruptly stopped Sativex after more than a year of continuous usage displayed no withdrawal symptoms meeting Budney’s criteria. While symptoms recurred after 7–10 days of abstinence from Sativex, prior levels of symptom control were readily re-established upon re-titration of the agent (Wade et al 2006).
Overall, Sativex appears to pose less risk of dependency than smoked cannabis based on its slower onset, lower dosage utilized in therapy, almost total absence of intoxication in regular usage, and minimal withdrawal symptomatology even after chronic administration. No known abuse or diversion incidents have been reported with Sativex to date (as of November 2007). Sativex is expected to be placed in Schedule IV of the Misuse of Drugs Act in the United Kingdom once approved.
Cognitive effects of cannabis have been reviewed (Russo et al 2002; Fride and Russo 2006), but less study has occurred in therapeutic contexts. Effects of chronic heavy recreational cannabis usage on memory abate without sequelae after a few weeks of abstinence (Pope et al 2001). Studies of components of the Halstead-Reitan battery with Sativex in neuropathic pain with allodynia have revealed no changes vs placebo (Nurmikko et al 2007), and in central neuropathic pain in MS (Rog et al 2005), 4 of 5 tests showed no significant differences. While the Selective Reminding Test did not change significantly on Sativex, placebo patients displayed unexpected improvement.
Slight improvements were observed in Hospital Anxiety and Depression Scales depression and anxiety scores were noted with Sativex in MS patients with central neuropathic pain (Rog et al 2005), although not quite statistically significant. No long-term mood disorders have been associated with Sativex administration.
Debate continues with regard to the relationship between cannabis usage and schizophrenia (reviewed (Fride and Russo 2006)). An etiological relationship is not supported by epidemiological data (Degenhardt et al 2003), but if present, should bear relation to dose and length of high exposure. It is likely that lower serum levels of Sativex in therapeutic usage, in conjunction with anti-psychotic properties of CBD (Zuardi and Guimaraes 1997), would minimize risks. Children and adolescents have been excluded from Sativex RCTs to date. SAFEX studies of Sativex have yielded few incidents of thought disorder, paranoia or related complaints.
Adverse effects of cannabinoids on immune function have been observed in experimental animals at doses 50–100 times the psychoactive level (Cabral 2001). In four patients using herbal cannabis therapeutically for over 20 years, no abnormalities were observed in leukocyte, CD4 or CD8 cell counts (Russo et al 2002). Investigation of MS patients on Cannador revealed no major immune changes (Katona et al 2005), and similarly, none occurred with smoked cannabis in a short-term study of HIV patients (Abrams et al 2003). Hematological measures have been normal in all Sativex RCTs without clinical signs of immune dysfunction.
Concerns are frequently noted with new drug-drug interactions, but few have resulted in Sativex RCTs despite its adjunctive use with opiates, many other psychoactive analgesic, antidepressant and anticonvulsant drugs (Russo 2006a), possibly due to CBD ability to counteract sedative effects of THC (Nicholson et al 2004). No effects of THC extract, CBD extract or Sativex were observed in a study of effects on the hepatic cytochrome P450 complex (Stott et al 2005b). On additional study, at 314 ng/ml cannabinoid concentration, Sativex and components produced no significant induction on human CYP450 (Stott et al 2007). Thus, Sativex should be safe to use in conjunction with other drugs metabolized via this pathway.
The Marinol patient monograph cautions that patients should not drive, operate machinery or engage in hazardous activities until accustomed to the drug’s effects (http://www.solvaypharmaceuticals-us.com/static/wma/pdf/1/3/1/9/Marinol5000124ERev52003.pdf). The Sativex product monograph in Canada (http://www.bayerhealth.ca/display.cfm?Object_ID=272&Article_ID=121&expandMenu_ID=53&prevSubItem=5_52) suggests that patients taking it should not drive automobiles. Given that THC is the most active component affecting such abilities, and the low serum levels produced in Sativex therapy (vide supra), it would be logical that that patients may be able to safely engage in such activities after early dose titration and according to individual circumstances, much as suggested for oral dronabinol. This is particularly the case in view of a report by an expert panel (Grotenhermen et al 2005) that comprehensively analyzed cannabinoids and driving. It suggested scientific standards such as roadside sobriety tests, and THC serum levels of 7–10 ng/mL or less, as reasonable approaches to determine relative impairment. No studies have demonstrated significant problems in relation to cannabis affecting driving skills at plasma levels below 5 ng/mL of THC. Prior studies document that 4 rapid oromucosal sprays of Sativex (greater than the average single dose employed in therapy) produced serum levels well below this threshold (Russo 2006b). Sativex is now well established as a cannabinoid agent with minimal psychotropic effect.
Cannabinoids may offer significant “side benefits” beyond analgesia. These include anti-emetic effects, well established with THC, but additionally demonstrated for CBD (Pertwee 2005), the ability of THC and CBD to produce apoptosis in malignant cells and inhibit cancer-induced angiogenesis (Kogan 2005; Ligresti et al 2006), as well as the neuroprotective antioxidant properties of the two substances (Hampson et al 1998), and improvements in symptomatic insomnia (Russo et al 2007).
The degree to which cannabinoid analgesics will be adopted into adjunctive pain management practices currently remains to be determined. Data on Sativex use in Canada for the last reported 6-month period (January-July 2007) indicated that 81% of prescriptions issued for patients in that interval were refills (data on file, from Brogan Inc Rx Dynamics), thus indicating in some degree an acceptance of, and a desire to, continue such treatment. Given their multi-modality effects upon various nociceptive pathways, their adjunctive side benefits, the efficacy and safety profiles to date of specific preparations in advanced clinical trials, and the complementary mechanisms and advantages of their combination with opioid therapy, the future for cannabinoid therapeutics appears very bright, indeed.