Peripherally Restricted Cannabinoids for the Treatment of Pain

Abstract

The use of cannabinoids for the treatment of chronic diseases has increased in the United States, with 23 states having legalized the use of marijuana. Although currently available cannabinoid compounds have shown effectiveness in relieving symptoms associated with numerous diseases, the use of cannabis or cannabinoids is still controversial mostly due to their psychotropic effects (e.g., euphoria, laughter) or central nervous system (CNS)-related undesired effects (e.g., tolerance, dependence). A potential strategy to use cannabinoids for medical conditions without inducing psychotropic or CNS-related undesired effects is to avoid their actions in the CNS. This approach could be beneficial for conditions with prominent peripheral pathophysiologic mechanisms (e.g., painful diabetic neuropathy, chemotherapy-induced neuropathy). In this article, we discuss the scientific evidence to target the peripheral cannabinoid system as an alternative to cannabis use for medical purposes, and we review the available literature to determine the pros and cons of potential strategies that can be used to this end.

Overview of Marijuana and the Endocannabinoid System

Cannabis, or marijuana, is composed of dried and shredded flowers and leaves of the cannabis plant. It is derived mostly from the Cannabis sativa plant, but marijuana from other species, such as Cannabis indica or their hybrids, also exists. Resins that come from the cannabis plant, hashish or hash oil, contain more concentrated active ingredients than cannabis.¹ Abuse of marijuana may be due to the active ingredient delta-9-tetrahydrocannabinol, otherwise known as THC, which activates the endocannabinoid system through cannabinoid receptors.² If the concentration of THC is high enough, marijuana can produce acute effects such as cognitive impairment, sedation, euphoria, tachycardia, orthostatic hypotension, and anxiety or relaxation. Cannabidiol is another major component of cannabis that does not produce euphoria and has limited psychotropic effects.² Long-term use of marijuana can lead to an impairment in memory and learning abilities, and also, in a small genetically predisposed population, to the development of psychosis especially if started at a young age.³ In addition, marijuana can cause respiratory problems if it has been smoked regularly and chronically.

Currently, 107 different cannabinoids (unique constituents of the marijuana plant) have been identified in the hemp plant Cannabis sativa.¹ These compounds are similar to the endogenous cannabinoid group that consists of long-chain polyunsaturated fatty acids. Included in this system are enzymes responsible for degradation and synthesis of these endocannabinoids and cannabinoid receptors. The major endocannabinoids are anandamide and 2-arachidonoyl-glycerol (2-AG).² The endocannabinoid system also contains at least two well-characterized cannabinoid receptors: cannabinoid receptor type 1 (CB₁) and type 2 (CB₂). CB₁ receptors are mostly expressed in the brain but have limited distribution in peripheral tissues, whereas CB₂ receptors are mainly expressed in the peripheral tissues and immune cells. CB₂ receptors have also been found in glial cells in the central nervous system (CNS).⁴ The psychotropic effects of marijuana induced mostly by THC are mediated through the activation of central CB₁ receptors.

Currently, U.S. federal law classifies cannabis as a Schedule I substance deemed with high abuse potential and no acceptable medicinal use, but certain states have passed medical marijuana use acts for more than a decade due to studies refuting classification as a Schedule I drug. To date, 23 states and the District of Columbia have legalized marijuana in some form. The states of Colorado (2013), Washington (2013), Oregon (2014), Alaska (2015), and the District of Columbia (2015) have legalized cannabis for recreational purposes.

Medicinal Potential of Marijuana

Medicinal use of cannabis has been shown to be effective for certain disease states, and it has been used empirically for medicinal purposes for hundreds of years.² Controversy surrounding the use of medical marijuana stems from the psychoactive effects of THC and its abuse potential. Currently certain synthetic derivatives of THC are approved by the U.S. Food and Drug Administration (FDA).² Dronabinol is a synthetic derivative of THC, available in capsule form, approved by the FDA for treatment of chemotherapy-induced nausea and appetite stimulation in patients with acquired immunodeficiency syndrome (AIDS). Another synthetic THC derivative, nabilone, is also FDA approved for treatment of chemotherapy-induced nausea. Sativex (GW Pharmaceuticals, Cambridge, UK), approved in 20 countries but not including the United States, contains 27 mg/ml of THC and 25 mg/ml of cannabidiol in the form of an orobuccal spray for the treatment of spasticity or neuropathic pain associated with multiple sclerosis. Even though these cannabinoid compounds have been shown to be effective for different disease conditions, they all penetrate the CNS. This is why these compounds produce similar effects to marijuana when used for recreational purposes. This leads to the clinical question of whether novel cannabinoid formulations that only work peripherally—without CNS penetration—could be effective in disease states with prominent peripheral pathophysiologic mechanisms, such as chemotherapy-induced neuropathy, painful diabetic neuropathy, postherpetic neuralgia, postsurgical pain, and inflammatory pain. Theoretically, this approach would resolve the major liabilities of cannabinoids by removing the undesirable effects on the CNS.

Reasons to Avoid Central Nervous System Penetration

The acute psychotropic effects (e.g., euphoria, distortion of time and space, paranoia, laughter) of marijuana are a major cause of controversy for its medicinal use. However, regular or chronic use of cannabis can also present concerning central side effects. Potential side effects related to long-term cannabis use are of particular relevance because the medical conditions for which cannabis could provide clinical benefits are chronic diseases (e.g., neuropathic or cancer pain, spasticity due to multiple sclerosis, AIDS-related wasting syndrome). The regular or continuous (heavy) use of cannabis with high levels of THC (and potentially cannabis-based medications) results in the development of tolerance, and potentially dependence, addiction, or interactions with other analgesic medications (i.e., opioids).^5-10 These effects are known to have CNS mechanisms.

In a double-blind, placebo-controlled study conducted in heavy and occasional users of cannabis who were exposed to 500 μg/kg of THC, acute neurocognitive impairment was significantly higher in occasional users than in heavy users.⁵ This study indicates that regular use of cannabis results in the development of tolerance. Supporting this assumption, it has been demonstrated that downregulation of CB₁ receptors in chronic smokers also is higher when compared with occasional users of cannabis.⁶ This study also showed that downregulation of CB₁ receptors in chronic cannabis users is not generalized but, rather, selective to cortical brain areas, and interestingly, this phenomenon is reversed after 4 weeks of abstinence.⁶

Accordingly, we have shown that in rats with peripheral nerve injury, intrathecal injections of nonselective cannabinoid receptor agonist CP 55,940 induced tolerance to antinociceptive effects in rats.⁷ Furthermore, this chronic administration of CP 55,940 produced the development of tolerance to CB₂-specific agonist JWH015 injected intrathecally.⁴ The development of tolerance of cannabinoids, which seems to be more related to CB₁ receptors, could likely lead to higher levels of consumption of cannabis in regular users, which could be a factor that influences the development of dependence or even addiction in some users. In fact, tolerance, dependence, and addiction to cannabis (or to CB₁ receptor agonists) share some molecular mechanisms.⁸

It is well described in animal studies that both the endocannabinoid and opioid systems cross-communicate, interact, or influence each other.¹¹ Therefore, the interaction of cannabinoids with other analgesic drugs is another area of potential concern. This is thought to be due to the close physical proximity of cannabinoid and opioid receptor expression, or colocalization.¹² For example, CB₁ receptor activation contributes to the enhanced behavioral responses induced by morphine in a rat model of morphine sensitization.⁹ Morphine sensitization behaviors are associated with drug-seeking behaviors in rodents and are used to study the mechanisms of drug addiction.¹³ In fact, CB₁ receptor activation influences heroin-seeking behaviors in rats.¹⁴ In electrophysiologic studies, it has been shown that the exposure of adolescent (but not adult) rats to the nonselective cannabinoid agonist WIN55212-2 produces a long-lasting tolerance 14 days after drug exposure in brain dopamine neurons (reduction of neuronal activity), and this cannabinoid pretreatment also resulted in tolerance to morphine (ventral tegmental area), cocaine (ventral tegmental area), and amphetamine (midbrain).¹⁰ Behaviorally, it has been demonstrated that the chronic treatment of guinea pigs with systemic WIN55212-2 produces mechanical antinociceptive cannabinoid tolerance and also tolerance to morphine’s analgesic effects.¹⁵ The interaction between the endogenous cannabinoid and opioid systems could also provide beneficial outcomes. In fact, this has been demonstrated in humans. Vaporized cannabis enhances the analgesic effects of morphine in patients with chronic pain.¹⁶ These data are interesting but also strongly support the concern regarding the potential interactions between cannabinoids and opioids in humans, especially after chronic exposure of either one.

Cannabinoid compounds administered systemically for medical purposes could induce all these CNS-driven undesirable effects. This is problematic particularly in conditions in which the penetration of cannabinoids to the CNS may not be necessary, such as peripherally driven pain conditions.

Peripheral Cannabinoid Signaling and Modulation of Pain Signaling in Humans

The relevance of the endocannabinoid system in pain modulation has been extensively described. As mentioned earlier, CB₁ receptors are widely expressed in the CNS including several anatomic structures or cell types that process pain information. Cannabinoid receptors also are expressed in the periphery and modulate several cellular functions that could result in a reduction of the activity of the nociceptive pathways. For example, CB₁ and CB₂ receptors play an important role in the regulation of vasculature and endothelial cells by regulating blood-brain barrier function or reducing inflammatory processes.^17-19 Mast cells express cannabinoid receptors and also play a role in inflammation, and they are responsible for contributing to several inflammatory diseases such as atopic eczema, chronic urticaria, allergic asthma, and allergic rhinitis.²⁰ CB₂ receptors are expressed in fibroblast-like synoviocytes in patients with rheumatoid arthritis.²¹ In human skin biopsies, dermal fibroblasts have been shown to express CB₁ and CB₂ receptors.²² Whether cannabinoid receptors modulate immune responses in these cells is not yet clear.²² The modulation of the function of these peripheral cells through cannabinoid receptors could explain, in part, the analgesic effects observed in chronic pain conditions in humans because the molecules just mentioned are also involved in pain-processing functions (Tables 1 and 2).

Table 1.

Targets and Effects of Cannabinoids in Peripheral Human Cells and Structures Involved in Nociceptive Processes

Drug	Type of receptors involved in mediating drug effects			Cell targets and effects
	CB1 receptors	CB2 receptors	Other receptors
JWH133, O-1966 (CB2 agonists)		*		Modulation and restoration of altered blood-brain barrier functions during inflammatory conditions; reduction of proinflammatory factors (e.g., cytokines, chemokines, adhesive molecules, transcription factors) in macrophages and brain microvascular endothelial cells16, 18
N-arachidonyl dopamine (endocannabinoid, CB1/CB2 agonist)	*	*		Reduction of proinflammatory cytokines in endothelial cells17
WIN55212-2 (CB1/CB2 agonist)			*	Reduction of proinflammatory cytokines in endothelial cells17
Anandamide (endocannabinoid, CB1/CB2 agonist), Arachidonyl-2′-chloroethylamide (ACEA), AM251 (CB1 agonists)	*			Inactivates (reduction of proinflammatory state) mast cells19
HU-308 (CB2 agonist)		*		Reduction of cell proliferation and production of intracellular proinflammatory transcription factors (mitogen-activated protein kinases) and proinflammatory effector production (i.e., interleukin-6, matrix-metalloproteinases) in human fibroblast-like synoviocytes20

CB₁ and CB₂ = cannabinoid receptors types 1 and 2, respectively.

Table 2.

Types of Peripheral Cells Expressing CB₁ and/or CB₂ Receptors

Cell type	CB1 receptor	CB2 receptor
Endothelial cells, brain microvasculature endothelial cells	*	*17, 18
Macrophages		*18
Mast cells	*	–19
Fibroblasts-like synoviocytes		*20
Skin	*	*21

CB₁ and CB₂ = cannabinoid receptors types 1 and 2, respectively.

Preclinical Evidence of Peripheral Action of Cannabinoids in Pain Signaling

The spinal cord, dorsal root ganglia, and dorsal horn of rats contain numerous fibers that express CB₁ receptors, with a higher presence in the dorsal root ganglia.²³ CB₁ receptors are found distally to the dorsal root ganglia, suggesting their presence in the peripheral nervous system,²³ which is susceptible to be activated by peripheral cannabinoids.

Proalgesic and proinflammatory factors released by peripheral cells are modulated by cannabinoids. These factors can produce peripheral nociceptor sensitization and contribute to peripherally driven pain conditions. Therefore, the modulation of the production of these factors by cannabinoid receptor activation could also result in analgesic effects. The studies mentioned in Tables 1 and 2 using human tissues are in accordance with preclinical studies. The local application of cannabinoids could be a strategy directed to modulate these cell functions while avoiding the central undesirable effects. Cannabinoids, mostly through CB₂ receptors, reduce the production of proinflammatory factors and the migration of leukocytes to the site of injury or into the brain under inflammatory conditions^24-28 (Table 3). These findings are of particular relevance because the invasion of peripheral immune cells (neutrophils or lymphocytes) into the CNS contributes to the development of inflammatory and neuropathic pain conditions.^{29, 30} Pain modulation via CB₂ receptors is also exerted through other nonimmunologic mechanisms. For example, peripheral CB₂ activation can reduce pain-related behaviors in rodents by inducing the release of peripheral opioids from keratinocytes.³¹ This mechanism of action of CB₂ agonists argues for the efficacy of the local application of these compounds for localized peripheral pain conditions.

Table 3.

Effects of Cannabinoids in Proinflammatory and Proalgesic Factors in Animal Models

Drug	Type of receptors involved in mediating drug effects		Mode of administration	Effects and mode of administration	Animal model
	CB1 receptors	CB2 receptors
HU-308 (CB2 agonist)		*	Topical	Reduction of proinflammatory cytokines in a model of uveitis	Rat23
AM1241 (CB2 agonist)		*	Intravenous	Reduction of the activity of mesenteric afferent nerves induced by the proalgesic factor bradykinin	Mouse24
JWH-(CB2 agonist)		*	Intraperitoneal or subcutaneous	Reduction of the number of immune cells (activated T lymphocytes, natural killer cells, mast cells, neutrophils) in the mesenteric lymph nodes in a model of chronic colitis and reduction of neutrophil migration into the brain, which produces neuroprotection in a model of brain ischemia	Mouse25, 26
CP55,940 (CB1/CB2 agonist)		*	Intraperitoneal	Reduction of macrophage migration from previously treated rats with the cannabinoid in an in vitro migration model (migrate in the Boyden chamber)	Rat27

CB₁ and CB₂ = cannabinoid receptors types 1 and 2, respectively.

The enhancement of anandamide via fatty acid amide hydrolase (FAAH) inhibition (PF-04457845 or URB597) reduced peripheral nociceptor excitability in pain-related behaviors in a chemically induced osteoarthritis model in rats, but this reduction of pain has not been reproduced in patients with osteoarthritis.³²

URB597 (an FAAH inhibitor) has also been shown to reduce peripheral nociceptor sensitization in a murine model of chemotherapy-induced painful neuropathy (a chronic pain condition with predominant peripheral pathogenesis) by enhancing anandamide in skin and through CB₁ receptor activation.³³ This is reproduced by the administration of anandamide.³³ Similarly, in a model of chemotherapy-induced painful neuropathy, systemic administration of JZL184, an inhibitor of monoacylglycerol lipase (the enzyme that degrades 2-AG), reduces pain-related behaviors in mice via CB₁ receptors at the dorsal root ganglia (periphery) level.³⁴

The ex vivo activation of CB₁ receptors using arachidonoyl-2′-chloroethylamide (ACEA) reduces the nerve growth factor–induced transient receptor potential vanilloid type-1 (TRPV1) sensitization in peripheral nociceptors.³⁵ Accordingly, ACEA or methanandamide reduces peripheral nociceptor sensitization in rats, and their individual administration into the hind paw of rats attenuates mechanical allodynia and hyperalgesia via peripheral CB₁ (but not CB₂) activation in a model of chronic inflammatory pain.³⁶ The local administration (intraplanar injection) of ACEA (via CB₁ receptors) or anandamide (via CB₁ and CB₂ receptors) reduces pain-related behaviors in the formalin model in normal rats and in rats with diabetic neuropathy.³⁷ A similar effect has been shown with drugs that inhibit 2-AG hydrolysis, JZL 184, URB602, or by 2-AG administered locally (intraplantar) in the formalin model in rats.³⁸ The activation of both CB₁ and CB₂ receptors with nonselective agonists (WIN 55,212-2) also reduces peripheral nociceptor (C fibers) sensitivity in mice in a model of cancer pain, a chronic pain condition.³⁹

These data together demonstrate that the modulation of peripheral cannabinoid receptors has the potential to produce analgesia or reduce pain in acute or chronic pain conditions. This approach would theoretically reduce the CNS-driven undesirable effects of cannabinoids.

Strategies to Target the Endocannabinoid System at the Periphery

Two potential therapeutic approaches could be used to target the peripheral endocannabinoid system: the development of drugs that do not cross the blood-brain barrier that could be administered systemically, and the local or peripheral administration of low doses of drugs to the areas or source of the painful condition.

Chemically Modified Peripherally Restricted Cannabinoids

Currently a few chemically modified, peripherally restricted cannabinoids have been developed to minimize CNS effects. SAB378, naphthalene-1-yl-(4-pentyloxynaphthalen-1-yl) methanone, is a peripheral restricted CB₁ and CB₂ receptor agonist.⁴⁰ SAB378 tested in rats has good oral bioavailability and minimal and slow penetration to the CNS. The compound does not accumulate in the CNS and produces antihyperalgesic effects in a rat model of neuropathic pain by acting mainly on peripheral CB₁ receptors (but not CB₂ receptors) without inducing the neurologic effects of cannabinoids.⁴⁰

Ajulemic acid (TC-3 or IP-751) is a molecule with a similar chemical structure to THC that is restricted to the periphery.⁴¹ This compound has shown good oral bioavailability and the absence of typical cannabinoid-induced psychotropic actions in humans.⁴¹ In addition, it has proven to be effective in reducing neuropathic pain in patients when given orally (vs placebo) and has been shown to have antiinflammatory effects in animal models.⁴¹ Even though ajulemic acid exerts actions on peripheral CB₁ receptors,⁴² it also acts on peroxisome proliferator-activated receptor (PPAR)-γ.⁴³

SAD448 is another CB₁ agonist restricted to the periphery that minimally penetrates the brain following intravenous administration in mice. It has been shown to have antinociceptive effects and, interestingly, synergistic antinociceptive effects with opiates in mice.⁴⁴

It seems that SAB378, ajulemic acid, and SAD448 are restricted to the periphery due to CNS drug (pumps) transporters.⁴² Of interest, these three compounds have been shown to reduce spasticity in a murine model of multiple sclerosis.⁴² Even though multiple sclerosis is a painful condition that responds to cannabinoids, the American Academy of Neurology has expressed concern regarding the use of these compounds due to their CNS adverse effect profile.⁴⁵ Therefore, these peripherally restricted cannabinoids could represent a promising alternative.

AZ111713908 is a CB₁ agonist found minimally in the brain of rats and mice when given systemically (subcutaneously) and is devoid of typical cannabinoid CNS effects in these animals.⁴⁶ AZ111713908 displays antinociceptive effects in rodent models of inflammatory and neuropathic pain. Local (inflamed paw) administration of the drug and studies using CB₁ or CB₂ knockout animals have demonstrated that its effects are exerted via peripheral CB₁ receptors.⁴⁶

The peripherally restricted FAAH inhibitor (inhibitor of anandamide hydrolysis), URB937, is a chemically modified molecule that does not cross the blood-brain barrier after systemic administration (intraperitoneal).⁴⁷ URB937 does not interact directly with cannabinoid receptors. When URB937 is given systemically (intraperitoneal) it results in an increase in the bioavailability of anandamide in the periphery,⁴ and a reduction in pain-related behavior in murine models of visceral pain, neuropathic pain, and inflammatory pain.⁴⁷ Interestingly, URB937 has also displayed a reduction of Fos expression of spinal neuronal hyperactivity or pain information processing, suggesting that the activation of the peripheral endocannabinoid system in pain conditions could also prevent central mechanisms of pain.⁴⁷

Dermal Effects of Cannabinoids on Pain and Inflammation

Transdermal administration of a cannabinoid may be preferred to oral administration to reduce peak-related side effects, eliminate first-past metabolism, enhance rate control, and provide an alternative for patients who cannot take anything by mouth.⁴⁸ Certainly, THC has the ability to penetrate the human (and guinea pig) skin through a transdermal patch, as was shown in in vitro settings.⁴⁸ Topical application of the potent THC analog (CB₁ and CB₂ agonist) HU220 in humans has been demonstrated to reduce pain perception, allodynia, and hyperalgesia.⁴⁹ This demonstrates that this approach to treat pain conditions is a valid therapeutic option to minimize CNS side effects while achieving good pain relief.

Interestingly, the transdermal administration of THC increases fentanyl levels when the drugs are administered concurrently, and this induces analgesia and enhances the antinociceptive effects of fentanyl in hairless guinea pigs.⁵⁰ This shows that transdermal administration of cannabinoids could also be helpful in reducing the amount of opiates used to treat pain.⁵⁰ The use of lower doses of either cannabinoids or opioids would not only reduce CNS penetration but also minimize side effects such as tolerance or interactions with other medications.

Cannabidiol (a major active ingredient of marijuana that does not produce cannabinoid-induced neurotropic or euphoric effects) has been evaluated for its antiinflammatory actions. Transdermal administration of cannabidiol as a pretreatment blocked the inflammatory effects of carrageenan in mice.⁵¹ The role of cannabidiol in inflammation in human sebocytes has been demonstrated in an in vitro study.⁵² Cannabidiol reduced the production of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in lipopolysaccharide-stimulated sebocytes in vitro. In this study, it was shown that the antiinflammatory effects of cannabidiol are due to the inhibition of nuclear factor-κB via adenosine A2a receptor activation.⁵²

Synthetic cannabinoids WIN 55212-2 and CP 55,940 have also shown potential for transdermal delivery therapeutics.⁵³ As opposed to WIN 55212-2, CP 55,940 is significantly metabolized in the skin, suggesting that WIN 55212-2 is a better candidate for transdermal applications.⁵³ In fact, when applied topically, WIN 55212-2 reduces nociceptive reflexes (tail-flick) in rats when administered at the site of application via CB₁ receptors.⁵⁴ Despite the skin metabolism of CP 55,940, topical administration of the drug could be useful for local and acute pain relief.

Intradermal administration of the CB₂ receptor agonist AM1241 or the CB₁ receptor agonist AZ111713908 has also been shown to decrease local inflammation and pain-related behaviors in rats.^{46, 55}

It is worth noting that differential effects of cannabinoids have been described, and these alternative outcomes should be taken into consideration from a clinical/therapeutic perspective. For example, in a murine model of allergic contact dermatitis, topical application of THC was shown to reduce swelling and inflammation (cellular infiltration, T-cell production of IFN-γ, and epidermal keratinocyte production of CCL2 and CXL10).⁵⁶ Curiously, the antiinflammatory effects of topical THC in that study were independent of CB receptors.⁵⁶ An explanation for these observations might be the potential alternative receptor targets of cannabinoid agonists including endocannabinoids. It has been demonstrated that cannabinoids can actually bind and activate TRPV1, the PPARs, G-protein receptor 55 (GPR55), α-7 nicotinic receptors, and serotonin 5-HT₃ receptors.²² These multiple cannabinoid targets might enhance the potential therapeutic spectrum of this type of compound when administered topically or transdermally but also might produce unexpected effects. For example, THC is able to activate a subset of peripheral nociceptors via the transient receptor potential channel ANKTM1.⁵⁷ This potential THC effect seems to be clinically irrelevant because a potent THC analog (HU220) reduces pain in patients when applied topically.⁴⁹ Alternatively, it is likely that this THC effect depends on its low cannabinoid potency when compared with HU220 (a more potent compound would favor cannabinoid signaling and result in analgesia).

All these data together suggest that several local factors should be taken into consideration with cannabinoids when formulated to be delivered transdermally or topically for the treatment of pain. Factors such as local metabolism, unexpected effects, off-target effects, and actions on several receptors can influence the local cannabinoid analgesic effects. Overall, the current available scientific evidence supports an analgesic effect of cannabinoids that acts in the periphery.

Conclusion

The endocannabinoid system modulates nociceptive pathways and inflammation processes. In general, activation of the endocannabinoid system has been shown to reduce inflammation and pain (or nociceptive responses) through CB₁ and CB₂ receptors (or in some cases, other non-cannabinoid receptors). Due to the lipophilic nature of cannabinoids, the therapeutic effects of these compounds are generally associated with acute or long-term–related neurologic undesirable effects mostly dependent on CNS CB₁ receptors. Some advances have been made in the development of novel chemically modified cannabinoid molecules that are restricted to the periphery to avoid CNS-related side effects. Other approaches have shown the potential of local application (topical or transdermal routes) of cannabinoids to achieve analgesia and reduce CNS-related undesirable effects. However, more systematic studies (e.g., dose-response studies and studies evaluating positive control groups, pharmacokinetics, vehicle bases, or extended-release patches vs poultices or creams) are needed to determine the real potential of local delivery of specific molecules. It is reasonable to hypothesize an accepted level of efficacy in inflammatory pain or even in chronic pain conditions with predominant peripheral pathophysiologic mechanisms (e.g., chemotherapy- or diabetes-induced painful neuropathy, chronic postoperative pain, postherpetic neuralgia). Furthermore, because peripheral mechanisms precede central pathophysiologic changes, it is likely that some central neuropathic pain conditions could be responsive to peripherally acting cannabinoids. A significant proportion of patients with chronic pain (> 50%) do not experience pain relief with current treatments. Those patients who derive some therapeutic benefit with currently available drugs experience mild to moderate pain relief accompanied by adverse effects that limit drug compliance and lead to treatment termination. Current drugs for the treatment of chronic pain (gabapentin, pregabalin, antidepressants, and opioids) display intolerable CNS-related adverse effects. Peripherally restricted therapeutic approaches are available for the treatment of chronic pain. Lidocaine or capsaicin gels or patches are approved therapeutic options indicated for peripherally located chronic neuropathic pain with a certain level of efficacy and limited adverse effects. A similar approach using peripherally administered cannabinoids, which have a better efficacy and safety profile, could provide another option for the treatment of these types of chronic pain.