Canna~Fangled Abstracts

The Analgesic Potential of Cannabinoids

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J Opioid Manag. Author manuscript; available in PMC 2013 July 30.
Published in final edited form as:
J Opioid Manag. 2009 Nov-Dec; 5(6): 341–357.
PMCID:PMC3728280
NIHMSID:NIHMS491709

The Analgesic Potential of Cannabinoids

Jaseena Elikottil, MBBS,2 Pankaj Gupta, MD,2 and Kalpna Gupta, PhD1
See other articles in PMC that cite the published article.

Abstract

Historically and anecdotally cannabinoids have been used as analgesic agents. In recent years, there has been an escalating interest in developing cannabis-derived medications to treat severe pain. This review provides an overview of the history of cannabis use in medicine, cannabinoid signaling pathways, and current data from preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. Clinical and experimental studies show that cannabis-derived compounds act as anti-emetic, appetite modulating and analgesic agents. However, the efficacy of individual products is variable and dependent upon the route of administration. Since opioids are the only therapy for severe pain, analgesic ability of cannabinoids may provide a much-needed alternative to opioids. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis based medications deserves serious consideration to alleviate the suffering of patients due to severe pain.

Keywords: pain, cannabinoid, opioid, marijuana, cannabis, HIV/AIDS, cancer

Introduction

Cannabinoids are derivatives of Cannabis sativa, the hemp plant, which evolved in the temperate regions of Central Asia. The female plants produce a fragrant amber-colored resin that contains cannabinoids. Crushed cannabis seeds were used as food in Asia in the past, especially during famines, and continue to be used as baby food in sub-Saharan Africa. Cannabis continues to be incorporated into a variety of recipes, ranging from bhang (a recreational drink) in India, chocolates and dates in the Middle-East, and curries in Thailand. The distinguishing feature of cannabis is the psychoactivity of its derivatives. There are at least 60 active compounds than can be extracted from cannabis [1]: Δ9-tetrahydrocannabinol (Δ9-THC) being the main one; others include cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabivarin (THCV), cannabichromene (CBC), etc. These compounds are responsible for the psycho-activity of cannabis products such as hashish, marijuana and hashish oil. The THC content of these varies from 5% in marijuana to 80 % in hashish oil [2].

Cannabis was used as a medicine in ancient China (2700 BC) and India (1000 BC)[13]. It was brought to Europe by Scythian invaders from Central Asia, entered Western medicine in early and middle 19th century and was widely used for its medicinal properties [3]. Cannabis extract and medications were marketed by pharmaceutical companies over-the-counter in the United States in late 19th to early 20th century. The accompanying increase in recreational marijuana smoking led to formation of the Marijuana Tax Act in 1937. Eventually, cannabis was omitted from the National Formulary and Pharmacopoeia. In the 1960s, the recreational use of cannabis peaked, followed by a renewal of scientific interest in the plant for its medicinal properties [4]. Since then cannabinoids have been studied or used in a multitude of applications, many of which relate to their potential use as analgesic agents.

Currently, opioids are the only analgesics for treating severe pain. However, in some patients, they are associated with rather unpleasant side effects, including sedation, loss of appetite, initial nausea, persistent constipation [5] and respiratory depression [6]. Moreover, issues such as tolerance, dependence and opioid induced hyperalgesia remain a major deterrent in opioid use [7]. In view of these side- effects and the decrease in analgesic efficacy over time [8], there is a need to explore alternative or adjunct medications to opioids in management of severe pain; and cannabinoids are being currently explored as one possible alternative. This review discusses the current and potential medicinal use of cannabinoids, especially for pain management, and considers whether they should be explored as a feasible adjunct or alternative to opioids, based on current data from experimental and clinical studies.

Classification of cannabinoids

Based on their origin, cannabinoids are classified into 3 categories: phytocannabinoids (plant origin), endocannabinoids (present endogenously in human or animal tissues) and synthetic cannabinoids. Tables 1​,22 and ​and33 list the common cannabinoids and their receptors with which they interact on the cell surface.

Table 1

Phytocannabinoids*
Table 2

Endocannabinoids*
Table 3

Synthetic Cannabinoids*

Cannabinoid receptors and signaling pathways

Cannabinoids mainly act via 2 different receptors: (i) the cannabinoid-1 (CB-1) receptor, predominantly expressed on the neurons; and (ii) the cannabinoid-2 (CB-2) receptor, predominantly expressed on cells of the immune system [9]. However CB-2 receptor expression is seen on glial as well as neuronal cells in several areas of the brain [10]. In the neurons, CB-1 receptors are preferentially located in the presynaptic areas and are seen more often on the inhibitory neurons than the excitatory ones [11]. The pattern of distribution suggests that the psychotropic effects are mediated mainly via the CB-1 receptors. CB-1 receptors are present in high levels in hippocampus (particularly in the dentate molecular layer and the CA3 region), lateral part of the striatum, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata, and cerebellar molecular layer. The thalamus and the brainstem are characterized by low levels of CB-1 receptor expression, which is consistent with the non-lethality of cannabinoids. In the spinal cord, moderate expression in seen in the dorsal horn [10].

Cannabinoid receptors are 7-transmembrane G-protein coupled receptors (GPCR) [12]. Ligand binding to CB-1 receptors results in inhibition of adenylyl cyclase and the voltage activated calcium (Ca2+) channels. Activation of CB-1 receptors thus decreases cAMP production and Ca2+ conductance, while increasing potassium conductance and the activity of mitogen-activated protein kinases (MAPK). Binding of cannabinoids to CB-1 receptors is critical to their antinociceptive activity. CB-1 receptor activation suppresses the nociceptive sensitization by influencing the release of neurotransmitters including acetylcholine, norepinephrine, gamma-amino butyric acid (GABA), glycine, dopamine, serotonin and cholecystokinin (CCK) from the presynaptic terminal, possibly through blunting of membrane depolarization and exocytosis via modification of the calcium and potassium channels [11], [13]. The modulation of intracellular calcium levels by CBD in neuronal cells appears to occur by using the mitochondria as a reservoir [14]. CB-2 receptor activation also inhibits adenylyl cyclase, but does not influence ion conductance [15]. Cannabinoids are suggested to bind some other types of receptors as well [16]. The transient receptor potential vanillloid 1 (TRPV1) receptor is present on sensory neurons and responds to nociceptive stimuli, however it is also present in the brain where it binds anandamide [17]. GPR 55 is an orphan G protein coupled receptor that is currently being explored as a cannabinoid receptor. It binds Δ9-THC, CP-55940, and endocannabinoids including anandamide [11] The 5HT-3 and NMDA receptors have also been implicated in cannabinoid signaling [11].

Cannabinoids modulate both the cell proliferation as well as cell survival pathways, albeit sometimes effects may be opposite depending on the cell type (Figure 1). Cannabinoids regulate the cell cycle via their effects on different members of the MAPK family, and PI3k/Akt pathways [18], [19] in neurons. On the contrary, cannabinoids also promote apoptosis through activation of JNK [20] and inhibition of ERK and PI3k/Akt [21], [22] pathways in cancer cells. Other studies also show a selective inhibitory effect of cannabinoids on cancer cells, while sparing normal cells [23],[24]. Cannabinoids influence sphingolipid-metabolizing pathways to induce sphingomyelin breakdown and generate ceramide [13]. The increased ceramide [25] via inhibition of PI3k inhibits PKB/Akt and ERK pathways, resulting in apoptosis [22]. THC also causes p8 upregulation via ceramide; p8 is a transcription factor with a regulatory role in the apoptotic cascade [26]. However, CB-2 antagonist rimonabant induces G1/S arrest and inhibits cell proliferation in breast cancer cells, though apoptosis or necrosis is not observed [27]. CB-2 agonist JWH-015 inhibits cisplatin-induced apoptosis in auditory cell lines [28]. Hence cannabinoids appear to have complex effects on the cell-cycle, which have not yet been completely defined. However, it appears that the cannabinoid signaling is cell-specific and may also be dependent upon specific agonists used. Importantly, this variability in cell signaling induced by cannabinoids in neuronal and non-neuronal cells suggests that the effect of cannabinoids will need to be examined for both their anti-nociceptive activity and the peripheral effect for individual pathological condition.

Figure 1

Cannabinoid receptor signaling leads to cell cycle regulation and potassium and calcium conductance. CB-1 receptor activation modifies the activity of calcium and potassium channels and the activity of intracellular protein kinases. Cannabinoids also

Routes of cannabinoid use

Smoking and oral ingestion are the common routes of cannabinoid use. Smoking results in rapid absorption and onset of psychoactive effects, and is the preferred mode of recreational use. Marijuana use is followed by a disruption of short-term memory, cognitive impairment, a sense of slowing of time, mood alterations, enhanced body awareness, reduced ability to focus, incoordination, and sleepiness [9]. Ingestion of hashish leads to delayed onset and longer duration of actions. THC can also be inhaled in a vaporized form without smoking, that avoids the inhalation of combustion by-products, while providing higher bioavailability. [2] When Δ9-THC enters the bloodstream, it is metabolized to 11-hydroxy Δ9-THC, which is absorbed into the adipose tissue, where it stays for 30 minutes before being released back into circulation and reaching the brain. [2]. In animal studies, both intraperitoneal and localized administration of cannabinoids have been used [29][30][31][32], [33]

Cannabinoids for analgesia – animal studies

a) Neuropathic pain

Cannabinoids have been studied in various types of neuropathic pain including nerve injury, chemotherapy-induced, diabetic neuropathy, etc. CB-1 receptors have been found to be upregulated in the thalamus [34] and the spinal cord [35] after nerve injury in rat models of neuropathic pain. Another study showed CB-2 receptors were induced in a localized area of spinal cord consistent with the location of nerve injury [36]. Systemic administration of both WIN-55,212-2 and HU-210 suppressed mechanical allodynia and thermal hyperalgesia in a rat model of trigeminal neuralgia [37]. WIN-55,212-2 also provided antinociception in a model of sciatic nerve injury, with enhanced action if administered pre-emptively [38]. Intrathecal JWH-133, a CB-2 agonist, also significantly improved mechanical allodynia after sciatic nerve injury [39]. Mechanical allodynia developing in diabetic rats also responds to WIN-55212-2 administration [40], as does thermal hyperalgesia and tactile allodynia induced in rats by the chemotherapeutic agent paclitaxel [41]. Mechanical allodynia induced by vincristine [42] and cisplatin [43] administration in rats is suppressed through both CB-1 and CB-2 receptor agonism. Pure CB-2 agonists also decrease chemotherapy induced neuropathic pain [44]. Furthermore, synergistic anti-nociceptive action between Δ9-THC, CBD and other extracts from cannabis in neuropathic pain has been suggested [45]. These studies demonstrate that cannabinoids can be potentially used as analgesics in treating neuropathic pain accompanying diverse pathologies.

b) Inflammatory pain

Both CB1 and CB2 receptors are involved in the mediation of inflammatory pain [46]. WIN-55,212-2 has been shown to attenuate the delayed phase of oro-facial pain induced by formalin injection in rats [47]. The action of WIN-55,212-2 in inflammatory pain appears to be mediated via both CB-1 and CB-2 receptors [48]. Systemic HU-308, a novel CB-2 agonist also attenuated inflammatory pain during hot plate test in mice [49]. Inflammatory pain and swelling in mouse hindpaw were relieved by systemic administration of both non-selective HU-210 and CB-2 selective JWH-133 [31], and also by local injection of CB-2 agonist AM1241 [32], [33]. Since, inflammatory pain is a hallmark of several chronic diseases including sickle cell disease and cancer, cannabinoids appear to be a promising therapy to treat severe pain in these diseases.

c) Cancer pain

Both endogenous and exogenous cannabinoids are being investigated for a role in cancer pain management. Cannabinoids have been found effective in increasing the threshold at which pain is perceived in tumor-afflicted mice [50]. Mechanical hyperalgesia in a murine model of bone cancer pain is associated with decreased anandamide levels in the affected area and was alleviated by local injection of anandamide. Hyperalgesia in this model was tested by measuring the paw withdrawal frequency in mice injected with fibrosarcoma cells into the calcaneum [29]. The cannabinoid agonist WIN-55,212-2 has also been shown to attenuate tumor induced hyeralgesia in mice, through peripheral action on CB-1 and CB-2 receptors, rather than by central action [51], [50]. Another study suggested that the antinociceptive action of WIN-55,212-2 in a mouse tumor model is solely via CB-1 receptors [48]. Systemic administration of CP-55,940 also attenuates tumor-induced hyperalgesia [30]. These studies suggest that different cannabinoids may offer pain relief in cancer by both systemic and peripheral routes, primarily via CB-1 receptors, and the route of administration may be tailored to the specific need.

The preclinical studies described above provide a rationale for further evaluation of cannabinoid receptor agonists in different types of pain. Both CB-1 and CB-2 receptors appear to be involved in pain modulation, and selective agonists may be useful when the specific role of each receptor is fully characterized in each type of pain. Especially in cases of pain attributable wholly or partly to inflammation, it may be worthwhile to explore a local route of administering the cannabinoid and thus avoid systemic side effects.

Synergism with opioids

a) Experimental studies

Opioids and cannabinoids both provide antinociception through G-protein coupled mechanisms, and many studies have explored synergistic interactions between them. A study using subcutaneous morphine and intraperitoneal THC in rats showed equivalent antinociception using high dose morphine or high dose THC or a low dose combination of both. In addition, the combination was shown to circumvent the development of tolerance when compared to either drug alone [52]. Pretreatment with HU-210 also increased the antinociceptive effect of morphine injected into the periaqueductal gray and prevented the development of tolerance [53]. Synergistic effect with an opioid-cannabinoid combination has been shown in other studies as well, using systemic [5455525657] or topical agonists [58]. THC also enhances the analgesic action of fentanyl and buprenorphine patches [59]. However, ultra-low dose naltrexone has also been shown to enhance the anti-nociceptive action of WIN 55,212-2, while high dose naltrexone does not [60]. This is similar to enhancement of the antinociceptive action of morphine by ultra-low concentrations of naloxone or naltrexone [61], [62]. Δ9-THC (both by itself and in combination with morphine) has been shown to provide better anti-nociception in diabetic mice than in non-diabetic arthritic mice, and this has been correlated to the lower endogenous opioid levels in diabetic mice [63]. CB-2 receptor activation by AM1241 causes the release of β-endorphin from keratinocytes, and the antinociceptive effect of AM1241 in rats is blocked by antagonism of the μ opiod receptor and by antiserum to β-endorphin [64]. Also, CB1 receptor knockout mice appear to have lesser opioid addiction and withdrawal [65], suggesting a role for cannabinoid receptors in opioid signaling pathways. Conversely, cannabinoid withdrawal symptoms were decreased in double μ and κ opioid receptor knockout mice [66], suggesting a relationship between opioid and cannabinoid receptor activities. These data support the harmonious and even supportive use of cannabinoids in conjunction with opioids. Clinical studies below support the experimental data on combined and/or simultaneous use of opioids and cannabinoids to treat pain.

b) Clinical studies

Most studies evaluating synergism between opioids and cannabinoids have been in healthy subjects, and the subject needs to be studied further in specific disease models. A double-blind randomized controlled trial evaluating 30 mg morphine or 20 mg Δ9-THC or a combination of both in experimental pain conditions in healthy human volunteers suggested a hyperalgesic effect of Δ9-THC when used alone, that disappeared when used with morphine [67]. A slightly additive analgesic action was observed with the THC-morphine combination when testing sensitivity to electric stimulation [67]. However, no synergism was noted in a randomized double blind study using adjuvant Δ9-THC in the acute post-operative pain in post prostatectomy patients on patient-controlled analgesia with opioid agonist piritramide [68].

Thus, adjunct use of cannabinoids may permit the use of lower doses of opioids than otherwise required, thus acting as an opioid sparing agent in similar situations. However, in other conditions, the addition of a cannabinoid may confer no additional benefit, so the optimal therapy for pain management in specific conditions remains an area for future research. Table 4 compares certain features of cannabinoids and opioids relevant to their use as antinociceptive agents.

Table 4

A comparision of opioids and cannabinoids in pain management

Cannabinoid as an Anti-emetic and Appetite stimulant

Currently dronabinol (synthetic Δ9-THC) and nabilone are approved for treatment of chemotherapy induced nausea and vomiting (CINV) [87]. From the patients’ perspective, nausea and vomiting is perhaps the most distressing effect of chemotherapy. While 5HT-3 receptor antagonists are effective for acute onset nausea and vomiting, they are not so beneficial in delayed nausea and vomiting. A recent systematic review concluded that nabilone is superior to placebo, domperidone and prochlorperazine in the management of CINV, but not superior to metoclopramide and chlorpromazine [88]. Oral dronabinol combined with prochlorperazine has been shown to be more effective than either agent alone in controlling CINV [89]. While many studies have shown dronabinol to improve mood, appetite and to decrease nausea in patients with AIDS or advanced cancer [90], a recent study comparing cannabis extracts (CE), Δ9-THC and placebo in patients with cancer related anorexia cachexia syndrome found no significant advantage of CE or Δ9-THC over placebo with regard to appetite, quality of life or toxicity [91].

Cannabinoids in HIV/AIDS

Many HIV infected patients smoke marijuana for a variety of reasons, including symptom relief and reducing symptom frequency; the users report improvement in appetite (97%), muscle pain (94%), nausea (93%), anxiety (93%), nerve pain (90%), depression (86%), and paraesthesia (85%). However, many cannabis users (47%) also reported associated memory deterioration. [92]. Smoked marijuana appears to have a beneficial role in reducing neuropathic pain in HIV, and the studies discussing this are detailed below. In a subanalysis of data from a multicountry randomized clinical trial studying self-care symptom management in HIV patients, anxiety was found to be lower in marijuana users than nonusers. Marijuana offered slightly better overall relief then the prescription/OTC medications for a number of symptoms (including anxiety, depression, nausea, vomiting, diarrhea, neuropathy). Marijuana users reported better overall medication effectiveness than non-users, however it is unclear whether it is attributable to the euphoric effect of marijuana or a real synergism with the medications [93]. Thus, cannabinoids may have multiple therapeutic functions in both, the central nervous system and peripheral organ disease.

Cannabinoids In Multiple sclerosis

Many randomized clinical trials with cannabinoid medications have been conducted in multiple sclerosis (MS). Patients with multiple sclerosis have diverse types of pain: dysesthesias, back pain, muscle pain, etc; and each type of pain needs to be managed differently [94]. Cannabinoids have a role in relieving pain, spasticity, tremor, nocturia and improving general well being in MS (Table 5). The non-psychotropic cannabinnoid HU-211 has been shown to decrease clinical signs and improve survival in rats with MS [90]. Cannabinoids, especially endocannabinoids and CB-2 agonists are postulated to protect against neuro-inflammation, and may thus be beneficial for management of MS [90]. A randomized controlled trial with 667 MS patients using oral Δ9-THC or a cannabis extract Cannador®; found subjective improvement in subjects’ self-reported sense of spasticity and pain, but no objective improvement in spasticity [95] by the Ashworth scale, [96]. No difference was noted between Δ9-THC and Cannador®[95]. Sativex® is an oromucosal spray containing Δ9-THC (27 mg/mL) and cannabidiol (CBD)(25 mg/mL), with a dosage of 100 μL/spray [97]. It was found to decrease mean pain intensity and reduce sleep disturbance in MS [98]. A 2 yr open label study as a follow up of this trial using Sativex® in 63 MS patients showed it to be effective in decreasing pain, however less than half of the subjects completed the trial [99]. Oral dronabinol achieved a modest reduction in pain intensity in MS and related conditions [100]. However, another study found no benefit from either Δ9 THC or a cannabis extract containing both THC and CBD [101]. Yet, a metanalysis of cannabis based medications in MS and other types of neuropathic pain concluded that cannabinoids were superior to placebo [102]. All these studies found dizziness to be the most common adverse effect, and that the incidence was higher in the treatment groups. Overall, cannabinoids appear to be effective in treating pain in MS, and would need to be further evaluated for their optimum use in MS.

Table 5

Clinical Studies with Cannabinoids in Multiple Sclerosis

Clinical studies with cannabinoids in pain

The trials focusing on MS and related etiologies have already been discussed above. The text below focuses on clinical studies using cannabinoids in other conditions associated with pain. Further details of these studies and other clinical trials using cannabinoids are discussed in Tables 6 & 7. Studies using smoked cannabis in HIV associated sensory neuropathy and other types of neuropathic pain have found that it offers clinically significant analgesia to a large number of subjects [112], [114115] but often with associated neurocognitive and psychoactive effects, especially at higher doses [115]. Improvement was noted in pain, mood and daily functioning [112], but not in evoked pain [115]. Sativex® was found to offer significant pain relief, as well as improvement in sleep and allodynia in neuropathic pain of various etiologies [116]. A randomized, double-blind, placebo-controlled crossover trial of different cannabis based medicinal extracts (THC only, CBD only, THC + CBD) was undertaken on a set of 34 patients with chronic pain (mainly neuropathic) uncontrolled by their usual medications. It showed improvement in control of pain and an improved quality of sleep in all, while the psychoactive effects were noted to be manageable [118]. Sativex® and a THC predominant cannabis extract GW-2000-02 both offered significant analgesia in subjects with neuropathic pain from brachial plexus avulsion [113]. However, a study comparing escalating daily doses of nabilone (maximum 2 mg) and dihydrocodeine (maximum 240mg) in patients with severe neuropathic pain found dihydrocodeine to offer clinically significant pain relief to more patients than nabilone; interestingly, no subject responded to both agents [117]. In cancer patients, nabilone provided multi-symptom relief, including pain relief, as compared to patients who did not receive nabilone [106]. As an adjuvant drug added to opioids, it also improved pain control and the quality of sleep in patients with chronic non-cancer pain [107]. A systematic review in 2001 of all randomized controlled trials done with cannabinoids in various types of pain concluded that in cancer pain, cannabinoids were of the same efficacy of codeine, while being associated with dose limiting CNS depressant effects [119]. A recent review of the clinical trials conducted with Sativex® and other cannabis extracts in various types of pain observed a benefit in a range of conditions, including MS, cancer, irritative urinary symptoms, neuropathy, peripheral nerve injury and spinal cord injury. The only condition where benefit was not noted was post-herpetic neuralgia [97]. Δ9-THC has analgesic and other beneficial effects in fibromyalgia and rheumatoid arthritis as well [110], [111]. Interestingly, studies in healthy human volunteers using oral cannabis extracts in acute pain models do not show any analgesic effect, but rather suggest a hyperalgesic action [85]. Studies regarding the use of cannabinoids for post-operative analgesia suggest that while cannabis extract Cannador® might potentially be beneficial [108], Δ9-THC offers no benefit and may actually provoke hyperalgesia [84], [109]. Therefore, different cannabis-derived drugs appear to have differences in effectiveness in treating pain and/other symptoms in a variety of diseases. The effort needs to be targeted to identify disease and symptom-specific therapeutic potential of specific cannabis-derived drugs.

Table 6

Clinical Studies with Cannabinoids in Non-Neuropathic Pain
Table 7

Clinical Studies with Cannabinoids in Neuropathic Pain

Can Cannabinoids be useful in Sickle cell disease?

We did not find any studies evaluating cannabinoids as analgesic agents in sickle cell disease (SCD). However, a questionnaire-based study evaluating the prevalence and reasons for marijuana use in SCD patients found that 31 of the 84 respondents reported cannabis use. While cannabis use was not found to vary with the severity of the disease, 52% of the users said they used it to reduce or prevent acute or chronic pain; other reasons were to improve sleep, mood or to aid relaxation [120]. Pain in SCD is a result of vascular occlusion, tissue infarction and inflammation [121], and is widely prevalent and often undertreated [122]. Currently used analgesics in SCD include acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, ketorolac, corticosteroids, tramadol and adjuvant agents. SCD patients with chronic pain are generally treated with a long acting opioid with addition of short acting opioids for breakthrough pain [121] Patients being treated with opiods for acute pain often suffer from nausea and vomiting [123]. Cannabinoids are commonly used to control nausea and vomiting in other settings, and could be potentially beneficial in this scenario as well. Cannabinoids, endocannabinoids and non-cannabinoid derivatives of the cannabis plant have also been found to have anti-inflammatory properties [124], which may be helpful in SCD. Transgenic sickle mice have been found to be markedly sensitive to ischemia-reperfusion injury [125]. CB-2 receptor activation by JWH-133 has been found to protect from cardiac ischemia reperfusion injury [126], [127] and may help in SCD as well. CB-2 receptor activation and CB-1 receptor inhibition has beneficial effects in cerebral ischemia [128], [129]. Vasocclusion being the pathology behind the pain in SCD, these factors should be considered when evaluating the role of cannabinoids as analgesics in this condition. Since SCD is a condition where the patient suffers severe acute episodes superimposed on a background of chronic lifelong pain, newer modalities need to be investigated to help achieve a better quality of life. Cannabinoids could possibly be used as adjunct agents along with opioids to decrease opioid dose and achieve better pain control. They also possess the potential to favorably modify the disease process via various mechanisms of central and peripheral activity discussed above.

Side effects of cannabinoids

Epidemiological studies have reached diverse conclusions regarding the association of cannabis with various cancers. A case-control study showed no increase in risk of head and neck cancer with cannabis use [130]. Some studies show higher lung cancer rates in marijuana smokers [131], [132], while some do not find any such association [133]. Maternal marijuana use, especially in the first trimester, is associated with an increased risk of neuroblastoma in the child [134]. Marijuana smoke has been shown to be mutagenic [135136], while THC by itself is not mutagenic [137138]. Equivocal proof of carcinogenicity of THC in B6C3F1 mice was found by one study [139]. These mice when treated with THC for 2 years showed an increased incidence of thyroid follicular cell adenoma [139140]. In contrast, THC was found to increase apoptosis and improve survival in murine cancer models and in human lymphoma and leukemia [141]. Moreover, the cannabinoid HU-331 is anti-angiogenic in vivo and vitro, suggestive of an inhibitory effect on cancer progression [142]. It appears that cannabinoids may have two opposite effects on cancer: tumor regression via promotion of apoptosis, and tumor promotion via suppression of immunogenicity [13]. Δ9-THC has been shown to inhibit angiogenesis and cell cycle progression in tumor cell lines, especially in glioma cells [14383]. WIN-55,212-2 and other cannabinoid agonists have been suggested as potential therapeutic options in prostate cancer [144]. It appears that past conflicting epidemiological data regarding association of marijuana smoking and cancer may not necessarily apply to Δ9–THC and other cannabis derivatives during therapeutic use via a non-inhalational route; however, caution may still be exercised while awaiting conclusive data.

Cannabinoids obviously have a potential to be misused and carry the risk of addiction. Prior psychiatric evaluation before prescribing cannabinoids has been suggested as one way to decrease this risk. Cannabis use in adolescence and young adulthood may have lasting effects on the brain and behavior [145]. Marijuana smoking has been postulated to contribute to the development of schizophreniform disorders [146], besides the risk of brief psychotic features with acute use [147], especially in the adolescent population. Diminished cognitive function in adolescent cannabis users [148] is also an area of concern. Chronic cannabis users are also at risk of developing the amotivational syndrome, characterized by apathy, lack of activity, incoherence, blunting of cognition and affect [90]. However, all this data is from marijuana users, and not from a controlled therapeutic use of cannabinoids. It cannot be said for certain that long-term therapeutic use of cannabinoids will show the same risks. An 8 week study of cognition in patients with multiple sclerosis on Sativex® did not show any worsening of cognition, however it did suggest that at higher doses, psychopathological problems may occur [149]. Some preclinical studies also show development of tolerance to various actions of cannabinoids [150], including antinociception [151]. Recreational cannabis use is associated with a withdrawal syndrome consisting of tiredness, yawning, depression, anxiety, psychomotor retardation, reported at a prevalence of 57.7 % among frequent cannabis users [152]. Cannabinoids have been reported to cause motor impairment in the form of cerebellar incoordination [153], and the pathway appears similar to that of ethanol induced incoordination [154]. These concerns may need to be addressed while exploring the therapeutic use of cannabinoids.

Conclusion

Management of severe chronic pain is best done by a multi-pronged approach, individualizing it not just according to the disease but also according to patient preferences and their side effect profiles. Currently there is intriguing evidence from animal studies showing efficacy of cannabinoids as antinociceptive agents, however data from human studies is still emerging. Cannabinoids may form a useful adjunct to current analgesic drugs in many conditions, especially in low doses incapable of inducing hyperalgesia or other side effects. They can also be used as rescue drugs when opioid analgesia is ineffective or inadequate, or as opioid sparing agent. They also appear to antagonize several side effects of opioids, and the opioid-cannabinoid combination may become a very useful agent in the long-term management of severe pain. Preclinical data also suggest a beneficial effect of cannabinoids on the disease process in HIV, cancer, and MS. While smoked marijuana tends to be a controversial territory, evidence points to significant multi-symptom relief from it especially in HIV patients. Cannabis derived medications deserve to be investigated in rigorously designed studies so that their role in managing severe and chronic pain in various conditions can be more clearly defined. The legalization of medical marijuana would also enable more clinical trials in humans, and development of cannabis-derived drugs for multiple disease processes, in addition to treating severe pain. Moreover, examination of cannabinoids and their receptors may potentially lead to a new understanding of disease processes as well. Thus, the medical, as well as the general community, need to move beyond preconceived notions about cannabis, and focus on its potential advantages in treating a host of conditions, including severe pain.

Acknowledgments

The authors are thankful to Divyanshoo R Kohli, MD for critical review of the manuscript, and to Ms Carol Taubert for preparation of the document. This work is supported by NIH Grants HL68802 and CA109582 to KG.

References

1. Molleman A, Demuth DG. Cannabinoid signalling. Life Sci.2006;78(6):549–563. [PubMed]
2. Booth M. Cannabis: A History. 1. Thomas Dunne Books; 2004.
3. Mikuriya TH. Marijuana in medicine: past, present and future.Calif Med. 1969;110(1):34–40. [PMC free article] [PubMed]
4. Zuardi AW. History of cannabis as a medicine: a review. Rev Bras Psiquiatr. 2006;28(2):153–157. [PubMed]
5. Brown RT, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006;2(3):137–146.[PubMed]
6. Davis MP, Lasheen W, Gamier P. Practical guide to opioids and their complications in managing cancer pain. What oncologists need to know. Oncology (Williston Park) 2007;21(10):1229–38.discussion 1238. [PubMed]
7. Chang G, Chen L, Mao J. Opioid tolerance and hyperalgesia.Med Clin North Am. 2007;91(2):199–211. [PubMed]
8. Ballantyne JC, Shin NS. Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain. 2008;24(6):469–478.[PubMed]
9. Svizenska I, Dubovy P, Sulcova A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures–a short review.Pharmacol Biochem Behav. 2008;90(4):501–511. [PubMed]
10. Gong JP, Onaivi ES, Ishiguro H, et al. Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 2006;1071(1):10–23. [PubMed]
11. Kano M, Ohno-Shosaku T, Hashimotodani Y, et al. Endocannabinoid-mediated control of synaptic transmission.Physiol Rev. 2009;89(1):309–380. [PubMed]
12. Demuth DG, Molleman A. Cannabinoid signalling. Life Sci.2006;78(6):549–563. [PubMed]
13. Guzman M, Sanchez C, Galve-Roperh I. Control of the cell survival/death decision by cannabinoids. J Mol Med.2001;78(11):613–625. [PubMed]
14. Ryan D, Drysdale AJ, Lafourcade C, et al. Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci.2009;29(7):2053–2063. [PubMed]
15. Howlett AC, Breivogel CS, Childers SR, et al. Cannabinoid physiology and pharmacology: 30 years of progress.Neuropharmacology. 2004;47 (Suppl 1):345–358. [PubMed]
16. Sawzdargo M, Nguyen T, Lee DK, et al. Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Brain Res Mol Brain Res. 1999;64(2):193–198.[PubMed]
17. Starowicz K, Nigam S, Di Marzo V. Biochemistry and pharmacology of endovanilloids. Pharmacol Ther.2007;114(1):13–33. [PubMed]
18. Ozaita A, Puighermanal E, Maldonado R. Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain. J Neurochem. 2007;102(4):1105–1114. [PubMed]
19. Molina-Holgado F, Pinteaux E, Heenan L, et al. Neuroprotective effects of the synthetic cannabinoid HU-210 in primary cortical neurons are mediated by phosphatidylinositol 3-kinase/AKT signaling. Mol Cell Neurosci. 2005;28(1):189–194.[PubMed]
20. Lee YM, Uhm KO, Lee ES, et al. AM251 suppresses the viability of HepG2 cells through the AMPK (AMP-activated protein kinase)-JNK (c-Jun N-terminal kinase)-ATF3 (activating transcription factor 3) pathway. Biochem Biophys Res Commun.2008;370(4):641–645. [PubMed]
21. Greenhough A, Patsos HA, Williams AC, et al. The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Int J Cancer.2007;121(10):2172–2180. [PubMed]
22. Ellert-Miklaszewska A, Kaminska B, Konarska L. Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of Bad protein. Cell Signal. 2005;17(1):25–37. [PubMed]
23. Caffarel MM, Moreno-Bueno G, Cerutti C, et al. JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene.2008;27(37):5033–5044. [PubMed]
24. Carracedo A, Gironella M, Lorente M, et al. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 2006;66(13):6748–6755. [PubMed]
25. Gustafsson K, Christensson B, Sander B, et al. Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma. Mol Pharmacol.2006;70(5):1612–1620. [PubMed]
26. Carracedo A, Lorente M, Egia A, et al. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell. 2006;9(4):301–312. [PubMed]
27. Sarnataro D, Pisanti S, Santoro A, et al. The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism. Mol Pharmacol. 2006;70(4):1298–1306. [PubMed]
28. Jeong HJ, Kim SJ, Moon PD, et al. Antiapoptotic mechanism of cannabinoid receptor 2 agonist on cisplatin-induced apoptosis in the HEI-OC1 auditory cell line. J Neurosci Res.2007;85(4):896–905. [PubMed]
29. Khasabova IA, Khasabov SG, Harding-Rose C, et al. A decrease in anandamide signaling contributes to the maintenance of cutaneous mechanical hyperalgesia in a model of bone cancer pain. J Neurosci. 2008;28(44):11141–11152. [PMC free article][PubMed]
30. Hamamoto DT, Giridharagopalan S, DA, Simone DA. Acute and chronic administration of the cannabinoid receptor agonist CP 55,940 attenuates tumor-evoked hyperalgesia. Eur J Pharmacol. 2007;558(1–3):73–87. [PMC free article] [PubMed]
31. Elmes SJ, Winyard LA, Medhurst SJ, et al. Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Pain. 2005;118(3):327–335.[PubMed]
32. Quartilho A, Mata HP, Ibrahim MM, et al. Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology. 2003;99(4):955–960.[PubMed]
33. Nackley AG, Makriyannis A, Hohmann AG. Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience. 2003;119(3):747–757. [PubMed]
34. Siegling A, Hofmann HA, Denzer D, et al. Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain.Eur J Pharmacol. 2001;415(1):R5–R7. [PubMed]
35. Lim G, Sung B, Ji RR, et al. Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats.Pain. 2003;105(1–2):275–283. [PubMed]
36. Zhang J, Hoffert C, Vu HK, et al. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci.2003;17(12):2750–2754. [PubMed]
37. Liang YC, Huang CC, Hsu KS. The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain. Neuropharmacology. 2007;53(1):169–177.[PubMed]
38. Guindon J, Desroches J, Dani M, et al. Pre-emptive antinociceptive effects of a synthetic cannabinoid in a model of neuropathic pain. Eur J Pharmacol. 2007;568(1–3):173–176.[PubMed]
39. Yamamoto W, Mikami T, Iwamura H. Involvement of central cannabinoid CB2 receptor in reducing mechanical allodynia in a mouse model of neuropathic pain. Eur J Pharmacol.2008;583(1):56–61. [PubMed]
40. Dogrul A, Gul H, Yildiz O, et al. Cannabinoids blocks tactile allodynia in diabetic mice without attenuation of its antinociceptive effect. Neurosci Lett. 2004;368(1):82–86.[PubMed]
41. Pascual D, Goicoechea C, Suardiaz M, et al. A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats. Pain. 2005;118(1–2):23–34. [PubMed]
42. Rahn EJ, Makriyannis A, Hohmann AG. Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. Br J Pharmacol. 2007;152(5):765–777. [PMC free article][PubMed]
43. Vera G, Chiarlone A, Cabezos PA, et al. WIN 55,212-2 prevents mechanical allodynia but not alterations in feeding behaviour induced by chronic cisplatin in the rat. Life Sci. 2007;81(6):468–479. [PubMed]
44. Rahn EJ, Zvonok AM, Thakur GA, et al. Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats. J Pharmacol Exp Ther. 2008;327(2):584–591.[PMC free article] [PubMed]
45. Comelli F, Giagnoni G, Bettoni I, et al. Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved. Phytother Res. 2008;22(8):1017–1024.[PubMed]
46. Clayton N, Marshall FH, Bountra C, et al. CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain.2002;96(3):253–260. [PubMed]
47. Burgos E, Pascual D, Isabel Martin M, et al. Antinociceptive effect of the cannabinoid agonist, WIN 55,212-2, in the orofacial and temporomandibular formalin tests. Eur J Pain. 2009 [Epub ahead of print] [PubMed]
48. Kehl LJ, Hamamoto DT, Wacnik PW, et al. A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain. Pain.2003;103(1–2):175–186. [PubMed]
49. Hanus L, Breuer A, Tchilibon S, et al. HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci USA. 1999;96(25):14228–14233. [PMC free article][PubMed]
50. Guerrero AV, Quang P, Dekker N, et al. Peripheral cannabinoids attenuate carcinoma-induced nociception in mice.Neurosci Lett. 2008;433(2):77–81. [PMC free article] [PubMed]
51. Potenzieri C, Harding-Rose C, Simone DA. The cannabinoid receptor agonist, WIN 55, 212-2, attenuates tumor-evoked hyperalgesia through peripheral mechanisms. Brain Res.2008;1215:69–75. [PMC free article] [PubMed]
52. Smith PA, Selley DE, Sim-Selley LJ, et al. Low dose combination of morphine and delta9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. Eur J Pharmacol. 2007;571(2–3):129–137. [PMC free article] [PubMed]
53. Wilson AR, Maher L, MM, Morgan MM. Repeated cannabinoid injections into the rat periaqueductal gray enhance subsequent morphine antinociception. Neuropharmacology.2008;55(7):1219–1225. [PMC free article] [PubMed]
54. Jan CR, Schneider AS. Sodium-dependent calcium efflux from adrenal chromaffin cells following exocytosis. Possible role of secretory vesicle membranes. J Biol Chem. 1992;267(14):9695–9700. [PubMed]
55. Cox ML, Haller VL, Welch SP. Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat. Eur J Pharmacol. 2007;567(1–2):125–130. [PubMed]
56. Cichewicz DL, McCarthy EA. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003;304(3):1010–1015.[PubMed]
57. Smith FL, Cichewicz D, Martin ZL, et al. The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol. Pharmacol Biochem Behav.1998;60(2):559–566. [PubMed]
58. Yesilyurt O, Dogrul A, Gul H, et al. Topical cannabinoid enhances topical morphine antinociception. Pain. 2003;105(1–2):303–308. [PubMed]
59. Cichewicz DL, Welch SP, Smith FL. Enhancement of transdermal fentanyl and buprenorphine antinociception by transdermal delta9-tetrahydrocannabinol. Eur J Pharmacol.2005;525(1–3):74–82. [PubMed]
60. Paquette J, Olmstead MC. Ultra-low dose naltrexone enhances cannabinoid-induced antinociception. Behav Pharmacol. 2005;16(8):597–603. [PubMed]
61. Crain SM, Shen KF. Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment.Proc Natl Acad Sci USA. 1995;92(23):10540–10544.[PMC free article] [PubMed]
62. Shen KF, Crain SM. Ultra-low doses of naltrexone or etorphine increase morphine’s antinociceptive potency and attenuate tolerance/dependence in mice. Brain Res.1997;757(2):176–190. [PubMed]
63. Williams J, Haller VL, Stevens DL, et al. Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception. Eur J Pharmacol. 2008;584(1):78–86. [PubMed]
64. Ibrahim MM, Porreca F, Lai J, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA. 2005;102(8):3093–3098. [PMC free article] [PubMed]
65. Ledent C, Valverde O, Cossu G, et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science. 1999;283(5400):401–404.[PubMed]
66. Castane A, Robledo P, Matifas A, et al. Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice. Eur J Neurosci. 2003;17(1):155–159.[PubMed]
67. Naef M, Curatolo M, Petersen-Felix S, et al. The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain. 2003;105(1–2):79–88.[PubMed]
68. Seeling W, Kneer L, Buchele B, et al. Delta(9)-tetrahydrocannabinol and the opioid receptor agonist piritramide do not act synergistically in postoperative pain. Anaesthesist.2006;55(4):391–400. [PubMed]
69. Saboory E, Derchansky M, Ismaili M, et al. Mechanisms of morphine enhancement of spontaneous seizure activity. Anesth Analg. 2007;105(6):1729–35. table of contents. [PubMed]
70. Wallace MJ, Blair RE, Falenski KW, et al. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J Pharmacol Exp Ther.2003;307(1):129–137. [PubMed]
71. Wallace MJ, Wiley JL, Martin BR, et al. Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. Eur J Pharmacol. 2001;428(1):51–57. [PubMed]
72. Blair RE, Deshpande LS, Sombati S, et al. Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. J Pharmacol Exp Ther. 2006;317(3):1072–1078. [PMC free article] [PubMed]
73. Porreca F, Ossipov MH. Nausea and vomiting side effects with opioid analgesics during treatment of chronic pain: Mechanisms, implications, and management options. Pain Med. 2009 [Epub ahead of print] [PubMed]
74. Slatkin NE. Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting: beyond prevention of acute emesis.J Support Oncol. 2007;5(5 Suppl 3):1–9. [PubMed]
75. Sontineni SP, Chaudhary S, Sontineni V, et al. Cannabinoid hyperemesis syndrome: clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse. World J Gastroenterol.2009;15(10):1264–1266. [PMC free article] [PubMed]
76. Pattinson KT. Opioids and the control of respiration. Br J Anaesth. 2008;100(6):747–758. [PubMed]
77. Gardell LR, King T, Ossipov MH, et al. Opioid receptor-mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery. Neurosci Lett. 2006;396(1):44–49.[PubMed]
78. Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain. 2008;24(6):479–496. [PubMed]
79. Weber ML, Farooqui M, Nguyen J, et al. Morphine induces mesangial cell proliferation and glomerulopathy via kappa-opioid receptors. Am J Physiol Renal Physiol. 2008;294(6):F1388–F1397. [PubMed]
80. Arerangaiah R, Chalasani N, Udager AM, et al. Opioids induce renal abnormalities in tumor-bearing mice. Nephron Exp Nephrol. 2007;105(3):e80–e89. [PubMed]
81. Pan H, Mukhopadhyay P, Rajesh M, et al. Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death. J Pharmacol Exp Ther. 2009;328(3):708–714. [PMC free article][PubMed]
82. Gupta K, Kshirsagar S, Chang L, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res.2002;62(15):4491–4498. [PubMed]
83. Bifulco M, Laezza C, Gazzerro P, et al. Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review) Oncol Rep. 2007;17(4):813–816. [PubMed]
84. Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth. 2006;53(8):769–775.[PubMed]
85. Kraft B, Frickey NA, Kaufmann RM, et al. Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Anesthesiology. 2008;109(1):101–110. [PubMed]
86. Beaulieu P, Ware M. Reassessment of the role of cannabinoids in the management of pain. Curr Opin Anaesthesiol.2007;20(5):473–477. [PubMed]
87. Mechoulam R, Hanu L. The cannabinoids: an overview. Therapeutic implications in vomiting and nausea after cancer chemotherapy, in appetite promotion, in multiple sclerosis and in neuroprotection. Pain Res Manag. 2001;6(2):67–73. [PubMed]
88. Davis MP. Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain. Expert Opin Investig Drugs. 2008;17(1):85–95. [PubMed]
89. Lane M, Vogel CL, Ferguson J, et al. Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. J Pain Symptom Manage. 1991;6(6):352–359. [PubMed]
90. Kogan NM, Mechoulam R. Cannabinoids in health and disease. Dialogues Clin Neurosci. 2007;9(4):413–430.[PMC free article] [PubMed]
91. Strasser F, Luftner D, Possinger K, et al. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006;24(21):3394–3400. [PubMed]
92. Woolridge E, Barton S, Samuel J, et al. Cannabis use in HIV for pain and other medical symptoms. J Pain Symptom Manage.2005;29(4):358–367. [PubMed]
93. Corless IB, Lindgren T, Holzemer W, et al. Marijuana effectiveness as an HIV self-care strategy. Clin Nurs Res.2009;18(2):172–193. [PubMed]
94. Pollmann W, Feneberg W. Current management of pain associated with multiple sclerosis. CNS Drugs. 2008;22(4):291–324. [PubMed]
95. Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial.Lancet. 2003;362(9395):1517–1526. [PubMed]
96. Herndon RM. Handbook of Neurological rating scales. 2. Demos Medical Publishing; 2006.
97. Russo EB, Guy GW, PJ, Robson PJ. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers. 2007;4(8):1729–1743.[PubMed]
98. Rog DJ, Nurmikko TJ, Friede T, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005;65(6):812–819. [PubMed]
99. Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin Ther. 2007;29(9):2068–2079. [PubMed]
100. Svendsen KB, Jensen TS, FW, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ.2004;329(7460):253. [PMC free article] [PubMed]
101. Killestein J, Hoogervorst EL, Reif M, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS.Neurology. 2002;58(9):1404–1407. [PubMed]
102. Iskedjian M, Bereza B, Gordon A, et al. Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain. Curr Med Res Opin. 2007;23(1):17–24. [PubMed]
103. Hartrick CT, Kovan JP, Shapiro S. The numeric rating scale for clinical pain measurement: a ratio measure? Pain Pract.2003;3(4):310–316. [PubMed]
104. Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology. 1997;48(2):332–338.[PubMed]
105. Bruera EN, Kuehn N, Miller MJ, et al. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care. 1991;7(2):6–9. [PubMed]
106. Maida V, Ennis M, Irani S, et al. Adjunctive nabilone in cancer pain and symptom management: a prospective observational study using propensity scoring. J Support Oncol.2008;6(3):119–124. [PubMed]
107. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008;9(3):254–264. [PubMed]
108. Holdcroft A, Maze M, Dore C, et al. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management.Anesthesiology. 2006;104(5):1040–1046. [PubMed]
109. Buggy DJ, Toogood L, Maric S, et al. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106(1–2):169–172. [PubMed]
110. Skrabek RQ, Galimova L, Ethans K, et al. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008;9(2):164–173.[PubMed]
111. Blake DR, Robson P, Ho M, et al. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis.Rheumatology (Oxford) 2006;45(1):50–52. [PubMed]
112. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672–680.[PMC free article] [PubMed]
113. Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004;112(3):299–306. [PubMed]
114. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68(7):515–521. [PubMed]
115. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9(6):506–521. [PubMed]
116. Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain.2007;133(1–3):210–220. [PubMed]
117. Frank B, Serpell MG, Hughes J, et al. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ. 2008;336(7637):199–201.[PMC free article] [PubMed]
118. Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia. 2004;59(5):440–452. [PubMed]
119. Campbell FA, Tramer MR, Carroll D, et al. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ. 2001;323(7303):13–16. [PMC free article] [PubMed]
120. Howard J, Anie KA, Holdcroft A, et al. Cannabis use in sickle cell disease: a questionnaire study. Br J Haematol.2005;131(1):123–128. [PubMed]
121. Ballas SK. Pain management of sickle cell disease. Hematol Oncol Clin North Am. 2005;19(5):785–802. [PubMed]
122. Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008;148(2):94–101. [PubMed]
123. Shord SS, Chew L, Villano J. Evaluation of opioid induced nausea and vomiting in sickle cell disease. Am J Hematol.2008;83(3):196–199. [PubMed]
124. Burstein SH, Zurier RB. Cannabinoids, endocannabinoids, and related analogs in inflammation. AAPS J. 2009;11(1):109–119.[PMC free article] [PubMed]
125. Nath KA, Grande JP, Croatt AJ, et al. Transgenic sickle mice are markedly sensitive to renal ischemia-reperfusion injury. Am J Pathol. 2005;166(4):963–972. [PMC free article] [PubMed]
126. Montecucco F, Lenglet S, Braunersreuther V, et al. CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol.2009;46(5):612–620. [PubMed]
127. Defer N, Wan J, Souktani R, et al. The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy.FASEB J. 2009;23(7):2120–2130. [PubMed]
128. Hillard CJ. Role of cannabinoids and endocannabinoids in cerebral ischemia. Curr Pharm Des. 2008;14(23):2347–2361.[PMC free article] [PubMed]
129. Zhang M, Martin BR, Adler MW, et al. Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke. J Neuroimmune Pharmacol. 2009;4(2):249–259.[PMC free article] [PubMed]
130. Aldington S, Harwood M, Cox B, et al. Cannabis use and cancer of the head and neck: case-control study. Otolaryngol Head Neck Surg. 2008;138(3):374–380. [PMC free article][PubMed]
131. Aldington S, Harwood M, Cox B, et al. Cannabis use and risk of lung cancer: a case-control study. Eur Respir J.2008;31(2):280–286. [PMC free article] [PubMed]
132. Voirin N, Berthiller J, Benhaim-Luzon V, et al. Risk of lung cancer and past use of cannabis in Tunisia. J Thorac Oncol.2006;1(6):577–579. [PubMed]
133. Hashibe M, Morgenstern H, Cui Y, et al. Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. Cancer Epidemiol Biomarkers Prev. 2006;15(10):1829–1834. [PubMed]
134. Bluhm EC, Daniels J, Pollock BH, et al. Maternal use of recreational drugs and neuroblastoma in offspring: a report from the Children’s Oncology Group (United States) Cancer Causes Control. 2006;17(5):663–669. [PubMed]
135. Wehner FC, van Rensburg SJ, Thiel PG. Mutagenicity of marijuana and Transkei tobacco smoke condensates in the Salmonella/microsome assay. Mutat Res. 1980;77(2):135–142.[PubMed]
136. Busch FW, Seid DA, Wei ET. Mutagenic activity of marihuana smoke condensates. Cancer Lett. 1979;6(6):319–324.[PubMed]
137. Van Went GF. Mutagenicity testing of 3 hallucinogens: LSD, psilocybin and delta 9-THC, using the micronucleus test.Experientia. 1978;34(3):324–325. [PubMed]
138. Zimmerman AM, Stich H, San R. Nonmutagenic action of cannabinoids in vitro. Pharmacology. 1978;16(6):333–343.[PubMed]
139. NTP Toxicology and Carcinogenesis Studies of 1-Trans-Delta(9)-Tetrahydrocannabinol (CAS No. 1972-08-3) in F344 Rats and B6C3F1 Mice (Gavage Studies) Natl Toxicol Program Tech Rep Ser. 1996;446:1–317. [PubMed]
140. Chan PC, Sills RC, Braun AG, et al. Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice. Fundam Appl Toxicol. 1996;30(1):109–117.[PubMed]
141. McKallip RJ, Lombard C, Fisher M, et al. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood. 2002;100(2):627–634. [PubMed]
142. Kogan NM, Blazquez C, Alvarez L, et al. A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells. Mol Pharmacol. 2006;70(1):51–59. [PubMed]
143. Galanti G, Fisher T, Kventsel I, et al. Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells.Acta Oncol. 2008;47(6):1062–1070. [PubMed]
144. Sarfaraz S, Afaq F, Adhami VM, et al. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res.2005;65(5):1635–1641. [PubMed]
145. Schneider M. Puberty as a highly vulnerable developmental period for the consequences of cannabis exposure. Addict Biol.2008;13(2):253–263. [PubMed]
146. Hall W, Degenhardt L. Cannabis use and the risk of developing a psychotic disorder. World Psychiatry. 2008;7(2):68–71. [PMC free article] [PubMed]
147. Luzi S, Morrison PD, Powell J, et al. What is the mechanism whereby cannabis use increases risk of psychosis? Neurotox Res.2008;14(2–3):105–112. [PubMed]
148. Harvey MA, Sellman JD, Porter RJ, et al. The relationship between non-acute adolescent cannabis use and cognition. Drug Alcohol Rev. 2007;26(3):309–319. [PubMed]
149. Aragona M, Onesti E, Tomassini V, et al. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: A double-blind, placebo controlled, crossover study. Clin Neuropharmacol. 2008;32(1):41–47. [PubMed]
150. Maldonado R. Study of cannabinoid dependence in animals.Pharmacol Ther. 2002;95(2):153–164. [PubMed]
151. Hutcheson DM, Tzavara ET, Smadja C, et al. Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol. Br J Pharmacol.1998;125(7):1567–1577. [PMC free article] [PubMed]
152. Hasin DS, Keyes KM, Alderson D, et al. Cannabis withdrawal in the United States: results from NESARC. J Clin Psychiatry.2008;69(9):1354–1363. [PMC free article] [PubMed]
153. DeSanty KP, Dar MS. Cannabinoid-induced motor incoordination through the cerebellar CB(1) receptor in mice.Pharmacol Biochem Behav. 2001;69(1–2):251–259. [PubMed]
154. Dar MS. Cerebellar CB(1) receptor mediation of Delta(9)-THC-induced motor incoordination and its potentiation by ethanol and modulation by the cerebellar adenosinergic A(1) receptor in the mouse. Brain Res. 2000;864(2):186–194.[PubMed]
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