Novel drug treatments for pain in advanced cancer and serious illness: a focus on neuropathic pain and chemotherapy-induced peripheral neuropathy

Abstract

Drugs that are commercially available but have novel mechanisms of action should be explored as analgesics. This review will discuss haloperidol, miragabalin, palmitoylethanolamide (PEA), and clonidine as adjuvant analgesics or analgesics. Haloperidol is a sigma-1 receptor antagonist. Under stress and neuropathic injury, sigma-1 receptors act as a chaperone protein, which downmodulates opioid receptor activities and opens several ion channels. Clinically, there is only low-grade evidence that haloperidol improves pain when combined with morphine, methadone, or tramadol in patients who have cancer, pain from fibrosis, radiation necrosis, or neuropathic pain. Miragabalin is a gabapentinoid approved for the treatment of neuropathic pain in Japan since 2019. In randomized trials, patients with diabetic neuropathy have responded to miragabalin. Its long binding half-life on the calcium channel subunit may provide an advantage over other gabapentinoids. PEA belongs to a group of endogenous bioactive lipids called ALIAmides (autocoid local injury antagonist amides), which have a sense role in modulating numerous biological processes in particular non-neuronal neuroinflammatory responses to neuropathic injury and systemic inflammation. Multiple randomized trials and meta-analyses have demonstrated PEA’s effectiveness in reducing pain severity arising from diverse pain phenotypes. Clonidine is an alpha2 adrenoceptor agonist and an imidazoline2 receptor agonist, which is U.S. Federal Drug Administration approved for attention deficit hyperactivity disorder in children, Tourette’s syndrome, adjunctive therapy for cancer-related pain, and hypertension. Clonidine activation at alpha2 adrenoceptors causes downstream activation of inhibitory G-proteins (Gi/Go), which inhibits cyclic Adenosine monophosphate (AMP) production and hyperpolarizes neuron membranes, thus reducing allodynia. Intravenous clonidine has been used in terminally ill patients with poorly controlled symptoms, in particular pain and agitation.

Introduction

The improvement in life expectancy of patients with cancer and the common use of chemotherapy agents such as paclitaxel and oxaliplatin for lung, breast, pancreatic, colorectal, esophageal, and prostate cancer has led to a significant prevalence of neuropathic pain among patients living with cancer or in cancer survivorship. ¹ Bortezomib, Revlimid, and vinca alkaloids cause neuropathic sensory and motor symptoms in patients treated for hematologic malignancies.^{2 –6} In addition to chemotherapy, other anti-cancer treatments, including surgery and radiation therapy, may cause chronic pain, with a subset of patients experiencing neuropathic pain. Since cancer occurs in an older population, many patients have comorbid illnesses such as diabetes and may have had neuropathic pain before their cancer, which is worsened with treatment. Effective analgesics for cancer-induced neuropathic pain (CIPN) are few and far between. Duloxetine is the only analgesic that has demonstrated benefit in a randomized controlled trial. Gabapentin is ineffective. ⁷ Pregabalin lacks a randomized trial that tests its benefit against a placebo.

Neuropathic pain, in general, is difficult to treat. ⁸ There are a limited number of analgesic options outside of effective opioids. Tricyclic antidepressants and gabapentinoids are the main class of adjuvants used to treat neuropathic pain. Tricyclic antidepressants have significant side effects, and gabapentin and pregabalin potentiate the respiratory depression and sedation associated with opioids.^{9 –13} Gabapentinoids are subject to abuse potential and have a “drug-liking” effect. Novel agents with distinctly different mechanisms of action are needed and can genotype the mechanism causing the pain. Trials to validate may require a transition to mechanistically informed, personalized, and stratified trials. ¹⁴

Recent studies based upon preclinical animal models have used established medications with novel targets as analgesics for neuropathic pain, including CIPN. These drugs are haloperidol, miragabalin (available in Japan). palmitoylethanolamide (PEA), and clonidine. Each of these commercially available medications has a target that causes improved pain behaviors in animals (antinociception) or reduces pain severity in humans (analgesia). Miragabalin has analgesic mechanisms similar to gabapentinoids but has a distinctly different interaction with voltage-gated calcium channels that improve gabapentinoid responses and reduce side effects.

Neuropathic pain, which arises from damage to somatosensory neurons, is clinically manifested by allodynia (pain from innocuous stimuli), hyperalgesia (exaggerated response to usually painful stimuli), and spontaneous or continuous pain described as paresthesia or dysesthesia, or lightening-like unprovoked pain.^{15 –17} The correlation between animal pain behaviors and subjective pain responses in clinical trials is imperfect and sometimes leads to disappointing results in clinical trials. Each drug discussed in this review requires more rigorous clinical trial data before being adopted into standard practice.

Haloperidol

Introduction

Physicians know haloperidol as a classic antipsychotic that binds to D2 (dopamine) receptors, which are of questionable benefit in treating delirium but are an effective antiemetic.^18,19 Very few are aware that haloperidol is a high-affinity irreversible sigma-1 receptor antagonist with analgesic potential.^{20 –24}

Mechanism of action

Sigma-1 receptors are a unique class of receptors distinct from opioid receptors, single transmembrane receptors on the endoplasmic reticulum (ER) on mitochondria-associated membranes. ²⁵ In specific neurons (such as those at the spinal cord), sigma-1 receptors are clustered at ER membranes that abut postsynaptic plasma membranes. ²⁶ Under stress and neuropathic injury, sigma-1 receptors act as a chaperone protein, which downmodulates opioid receptor activities and opens several ion channels, exerting a role in pain transmission.^{27 –31} This presents a target to treat neuropathic pain. ³² Sigma-1 receptors are over-expressed in neuropathic pain and, when tonically active, are “anti-opioid” for mu (MOR) and kappa (KOR) receptors.^21,22,33,34 Activation of sigmoid-1 receptors reduces pain thresholds under pathologic conditions such as nerve injury but not in normal circumstances. ³⁵ Hence, sigma-1 receptor antagonists are unlikely to be effective in treating acute pain, but multiple preclinical studies have demonstrated that haloperidol reduces neuropathic pain behaviors in animals.^{28,36 –42}

Preclinical studies

Chemotherapeutic-induced neuropathic pain is reported to reduce sigma-1 receptor levels in the spinal cord. Paclitaxel-exposed Chinese hamster ovarian cells caused overexpression of sigma-1 receptors in clusters. In one study, the sigma-1 receptor agonist SA4503 inhibited neuropathy induced by oxaliplatin and paclitaxel. In a second study, a sigma-1 receptor antagonist given before paclitaxel reduced neuropathic pain in animals by preventing the upregulation of extracellular signal-regulated kinases.^43,44 Fluvoxamine, a sigma-1 receptor inducer and agonist, significantly reduced paclitaxel neuropathic pain and neurotoxicity.^{45 –47} Furthermore, activation of the sigma1R is necessary for developing the sensory nerve mitochondrial damage and neuropathic pain caused by paclitaxel. ⁴⁸ More preclinical studies are needed to explain the opposite findings found in these preclinical studies.

Preclinical studies: Comparison with gabapentin and morphine

Haloperidol is a very potent noncompetitive sigmoid-1 receptor blocker that has been shown to enhance gabapentin opioid analgesia in preclinical models and case studies.^{36,38,49 –56} In a chronic constrictive injury neuropathic model, male Wistar rats responded better to haloperidol than gabapentin. The combination of gabapentin and haloperidol produced synergistic antinociception. ⁴⁹ Haloperidol does not increase pain response latencies in normal rats but extends latencies to tail-flick responses in neuropathically injured animals. ⁵⁷ Haloperidol was given before morphine in animal models; dose-dependently improves the antinociceptive effect of morphine and reduces physical dependence.^36,58

Clinical studies

Clinically, there is only low-grade evidence that haloperidol improves pain when combined with morphine, methadone, or tramadol in patients who have cancer, pain from fibrosis, radiation necrosis, or neuropathic pain.^{51,55,56,59,60} Two clinical studies confirmed the lack of benefit of haloperidol when treating acute pain.^61,62

Evidence of potential clinical benefits from other sigma-1 receptor blockers for neuropathic pain

There is sufficient preclinical evidence and some low-grade clinical experience to suggest that haloperidol may be an effective analgesic for neuropathic pain as an adjuvant to opioid therapy. MR309, a novel selective sigma-1 receptor ligand, reduced the proportion of patients with severe chronic neuropathy (3.0% vs 18.2% with placebo; p = 0.046). The total amount of oxaliplatin delivered was greater in the active arm, however. In an animal model, the sigma-1 receptor antagonists BD-1063 or S1RA given 30 min before each paclitaxel dose prevented the development of cold and mechanical allodynia in mice.

Rationale for haloperidol in chemotherapy-related neuropathy

The acute administration of both sigma-1 receptor antagonists dose-dependently reversed both types of paclitaxel-induced chronic allodynia. Therefore, it would be reasonable to propose a randomized trial of haloperidol versus placebo or the combination of haloperidol plus duloxetine versus duloxetine alone in patients receiving either paclitaxel or oxaliplatin chemotherapy, with neuropathic pain as the primary outcome, and nausea and vomiting as secondary outcomes.

Rationale for combining haloperidol with morphine or gabapentin for cancer-related neuropathic pain

In patients with cancer neuropathic pain, a randomized trial of an opioid versus an opioid plus haloperidol or gabapentin/pregabalin alone versus gabapentin/pregabalin plus haloperidol should be considered. In preclinical studies, haloperidol did not increase the lethality of morphine. As a result, the combination of morphine and haloperidol may be safer than the combination of morphine and gabapentin. ⁶³ There may be a concern about combining methadone and haloperidol since both prolong the QTc interval. However, torsades de pointe from haloperidol occurs mostly at doses greater than 3 mg/day.^{64 –66}

Pharmacokinetics: The dose needed for analgesia

What haloperidol dose is needed to block sigma-1 receptors? In humans, haloperidol occupancy of sigma-1 receptors is high at relatively low doses. ⁶⁷ A dose of 10 mg by mouth occupies 65% of dopamine (D2) receptors, whereas a 3 mg binds to 80% of the central nervous system (CNS) sigma-1 receptors.^68,69 Haloperidol does not downmodulate sigma-1 receptor mRNA, so recovery will occur when the drug is stopped. ⁷⁰ A reduced haloperidol metabolite also readily crosses the CNS, binding and blocking sigma-1 receptors. ⁷¹

Side effects

Extrapyramidal side effects, including akathisia, bradykinesia, Parkinsonism, and tremor, can occur in 10% of treated individuals. Elevated liver function tests, depression, dizziness, and sedation (at high doses) occur in less than 10%. Prolongation of the QTc and torsades de pointes and the neuroleptic malignant syndrome occur in less than 0.1%.

Mirogabalin besylate

Introduction

Miragabalin is a gabapentinoid approved for the treatment of neuropathic pain in Japan since 2019.

Mechanism of action

So how is mirogabalin different from gabapentin and pregabalin, and why would it improve analgesia when neuropathic pain is unresponsive to other gabapentinoids? Similar to pregabalin, pregabalin is a ligand for the voltage-gated calcium channel subunit alpha2/delta1 and alpha2/delta2. Mirogabalin, like pregabalin, blocks presynaptic voltage-gated calcium channels, which prevents neurotransmitter release across the synapse. ⁷² The alpha2/delta1 subunit is upregulated in somatosensory dorsal horn neurons with neuropathic injury. ⁷³ In CIPN, the alpha2/delta2 complexes with an-methyl-d-aspartate receptors through the C-tail of the calcium channel unit, which increases the neurotransmitter traffic across the synapse. ⁷⁴ The result is enhanced excitatory postsynaptic responses significantly curtailed by mirogabalin. ⁷⁵

Pharmacodynamic differences between miragabalin and other gabapentinoids

Mirogabalin differs from pregabalin in several ways. Mirogabalin dissociates from the alpha2/delta1 subunit more slowly than gabapentin and pregabalin and is more selective for alpha2/delta1 than alpha2/delta2. ⁷² The dissociation constant (Kd) is four times lower than pregabalin (13.5 nM vs 62.5 nM), demonstrating a greater affinity and five times lower for the alpha2 delta2 subunit (22.7 nM vs 125 nM).^76,77 Dissociation from alpha2/delta2 is 11.1 h, whereas it is 1.4 h for pregabalin. ⁷⁶ The relative duration of binding differences between alpha2/delta1 and alpha2/delta2 between mirogabalin and pregabalin, which favors mirogabalin alpha2/delta1 interactions, may be an important margin to efficacy, benefits, and side effects. ⁷⁶ Alpha2/delta2 binding leads to gabapentinoid side effects, and alpha2/delta1 binding is necessary for analgesia. ⁷⁸ Supratherapeutic doses (fourfold to sevenfold) of mirogabalin are needed before experiencing a “drug-liking” effect, whereas” drug-like” effects of pregabalin occur at therapeutic doses. ⁷⁹

Clinical studies

In randomized trials involving 834 patients with diabetic neuropathy, miragabalin 30 mg daily significantly reduced pain over 14 weeks (p = 0.027), and analgesia was sustained over 52 weeks without serious side effects. Treatment-emergent side effects (somnolence, edema, and weight gain) occurred in 27%. ⁸⁰ In a second study of 763 patients with post-herpetic neuralgia, treatment mirogabalin doses of 15, 20, and 30 mg/day over 14 weeks. The pain was significantly improved over the placebo. A 52-week open extension of the study demonstrated no analgesic tolerance. Treatment emerging side effects occurred in 39.7%. ⁸¹ A third study involved 150 patients with spinal cord injury. Progressive mirogabalin doses from 10 to 30 mg daily significantly reduced pain intensity (p = 0.0001). The odds of experiencing a 30% reduction in pain was 1.91, and a 50% reduction at 2.52. ⁸² A fourth study involved 210 patients with central neuropathic pain. The dose was 15 mg twice daily. The short form of the McGill pain questionnaire significantly improved. Adverse effects were similar to those in other studies, including somnolence, edema, and dizziness. ⁸³

Comparison with other gabapentinoids

Mirogabalin has been compared to pregabalin in the treatment of CIPN and retrospective studies of patients with pancreatic cancer and oxaliplatin-induced neuropathy. Mirogabalin doses ranging from 10 to 30 mg daily and pregabalin doses of 75 to 150 mg/day were compared. Though baseline neuropathic pain was worse in those started on mirogabalin, pain significantly improved with miragabalin over 6 weeks (92.3%) compared with pregabalin (33.3%). ⁸⁴ In a single-arm prospective study involving 52 patients treated with paclitaxel, mirogabalin 10–30 mg daily reduced numerical rating scores (0 no pain, 10 severe pain) by 30%, with a mean change of 1.7 points. ⁸⁵ Mirogabalin has reduced pain, whereas pregabalin has failed to reduce pain or cause side effects, limiting pregabalin dosing.^84,86

Disadvantages to mirogabalin

There are disadvantages to mirogabalin. Mirogabalin does not effectively reduce pain associated with fibromyalgia.^87,88 Opioids do not appear to improve mirogabalin analgesia but do increase adverse effects.^77,89 Alcohol, benzodiazepines, and tramadol increase sedation when combined with mirogabalin. ⁹⁰

Pharmacokinetics

Mirogabalin is 85% bioavailable, with peak concentrations (T-max) occurring approximately 1 h after oral intake. The mean terminal plasma half-life ranges between 2.57 and 3.08 h, but as mentioned, the clinical effects are long-lasting due to its binding time to alpha2/delta1 receptors, so it is given twice daily. ⁹¹ Oral dosage forms available in Japan are 2.5, 5, 10, and 15 mg. The starting dose is 5 mg twice daily, slowly titrated over 45 days to a maximum of 15 mg twice daily, depending on response. ⁹² No dose adjustments are needed for a creatinine clearance greater than 50 mL/min per 1.73 m². Doses should be adjusted to 50% of normal for a creatinine clearance of 30–50 ml/min per 1.73 m² and 25% or a creatinine clearance of less than 30 mL/min per 1.73 m². ⁹³ Doses do not need to be adjusted for mild to moderate hepatic impairment. ⁹⁴ Mirogabalin does not interact with cytochrome P450 enzymes but is a substrate for organic anion transporter 1 and 2, organic cation transporter 2, and multidrug and toxin extrusion transporters. ⁹⁵

Side effects

The adverse effects commonly encountered with mirogabalin are dizziness (8%–16%), somnolence (6%–24%), and headache (6%–14%). Constipation, diarrhea, edema, fatigue, nausea, vomiting, and weight gain have rare side effects. ⁹⁶

Future randomized trials should include a comparison of miragabalin with duloxetine for CIPN.

Palmitoylethanolamide

Introduction

PEA belongs to a group of endogenous bioactive lipids called ALIAmides (autocoid local injury antagonist amides), which have a sense role in modulating numerous biological processes, particularly non-neuronal neuroinflammatory responses to neuropathic injury and systemic inflammation.^{97 –102}

Mechanism of action

PEA accumulates in tissues as a biological response to inflammation and increases in brain regions involved in nociception and the spinal cord in response to neurologic injury and inflammation.^{102 –110} PEA is formed from cell membranes in response to stress. The “on-demand” production targets mast cell activation, degranulation, and microglial responses to nerve injury. Downstream, it inhibits cytokine release and intra-nuclear transit of NF-κB, which prevents interleukin, tumor necrosis factor, and prostaglandin responses.^{97,102,105,110 –118} There is a delicate balance between ALIAmide lipid responses to neuropathic injury and the subsequent neuroinflammatory response to injury, determining neuropathic pain experiences. ⁹⁸

PEA targets multiple receptors as a modulator of pain

PEA has multiple targets: the orphan receptor GPR-55 as the principal one, vanilloid receptors, particularly TRPV-1 (the capsaicin receptor), and does indirectly interact with classical cannabinoid receptors (CB1, CB2) through increased anandamide levels (through competition with fatty acid amide hydrolase) and inhibits glutamatergic neurotransmission.^{119 –126} However, most evidence suggests that the antiallodynic and antihyperalgesic effects are related to peroxisome proliferator-activated receptor (PPAR) activation and mast cell degranulation and activation inhibition.^{105,111,113,127 –134} PPARs are a family of nuclear receptors that modulate inflammation by down-regulating inflammatory gene responses, thus impairing chemokine expression. PPAR agonists are a new class of analgesics that target non-neuronal reactions to neuropathic injury.^135,136

Preclinical studies

Multiple animal models have demonstrated the benefits of PEA in neuropathic injury. PEA reduced hypersensitivity to mechanical and thermal stimuli in neuropathically injured animals, and this reduction was dependent on PPAR and classic cannabinoid receptors. ¹³⁷ PEA in mice subjected to chronic constrictive injury-related neuropathic pain delayed mast cell recruitment and degranulation, abolished nerve growth factor activation, preserved the constricted nerve from degeneration, and reduced microglia numbers in the spinal cord, associated with pain reduction. ¹³⁸ PEA improved the pain behaviors associated with selective nerve injury in Sprague Dawley rats. ¹³⁹

PEA and preclinical studies of chemotherapy neuropathy

PEA has been effective in reducing CIPN in animals. Animals exposed to oxaliplatin were treated with PEA 30 mg/kg intraperitoneal. PEA prevented the hypersensitivity associated with oxaliplatin. In the spinal cord, there was reduced glia activation and improved neuropathic pain behaviors without interfering with oxaliplatin anticancer activity. ¹²⁹ In a second model, PEA (10 mg/kg) reduced pain behaviors from oxaliplatin, reduced hyperactive glia in the spinal cord, and prevented proinflammatory cytokine release from the spinal cord. This was due to the downmodulation of the NF-κB pathway. ¹⁴⁰ PEA reduced spinal cord and hippocampal neuroinflammation in animals exposed to paclitaxel. The PEA doses were 30 mg/kg. PEA also had an antianxiety and antidepressant effect noted in animals. The benefits were dependent upon the presence of PPAR and CB1 receptors. ¹⁴¹ Two other studies have demonstrated the benefits of PEA in preventing and treating paclitaxel-related pain in animals.^142,143

Clinical studies

Clinical studies have demonstrated the benefits of PEA. A randomized controlled trial compared PEA 600 mg/day with a placebo and found that patients with diabetic neuropathy improved in pain, sleep, and depression associated with reductions in circulating Il-6 and C-reactive protein (CRP). No side effects were noted. ¹⁴⁴ A second study involving patients with diabetic neuropathy used PEA 300 mg twice daily in a prospective study. There was a dramatic reduction in pain (p < 0.00001) without any adverse events or safety issues. ¹⁴⁵ A recent clinical study involved patients receiving neoadjuvant oxaliplatin or paclitaxel with neuropathy. They received a PEA supplement for 3 months. Motor and sensory subjective outcomes were measured. Objective neurologic outcomes included deep tendon reflexes and vibratory perception. After 3 months, the overall clinical benefit, which included stability or improvement, occurred in 64%–77% of patients. Objective improvement occurred in 40% of the paclitaxel patients and 31% of the oxaliplatin-treated patients. Deep tendon reflexes improved by 20% and 16.9%, respectively. The quality of life improved in 22%–24% of patients with oxaliplatin, and 37.5%–45.9% of patients treated with paclitaxel. Only 6%–15% were treated with other analgesics. ¹⁴⁶

A large number of clinical studies have used PEA for inflammatory or neuropathic pain with positive outcomes. Four recently published meta-analyses have demonstrated that PEA is an effective analgesic with side effects no greater than placebo compared to randomized trials.^{147 –150}

PEA in combination with other analgesics

PEA has been used in combination with other analgesics. In preclinical models, PEA improves opioid analgesia and delays analgesic tolerance.^151,152 PEA improves gabapentin and paracetamol analgesia.^151,153

Advantages to PEA

In all randomized trials, PEA had the same side effects as placebo.^144,154,155 PEA improves psychological depression and fatigue associated with COVID-19.^{156 –158} PEA in randomized trials is an effective adjuvant to the treatment of autism.^159,160

Pharmacokinetics

The pharmacokinetics of PEA are unknown. PEA has a high first-pass clearance as a highly lipophilic compound. ¹²⁴ The intestinal wall and liver contain hydrolytic enzymes involved in PEA metabolism. Micronized or ultra-micronized ultramicronized PEA appears to improve animal absorption. ¹⁶¹ The volume of distribution is quite large. PEA readily crosses into the CNS, accumulates within cells, and passes through cell membranes.^124,162 PEA binds to fatty acid binding protein 5 and thus competes for binding with anandamide. Also, PEA competes with anandamide metabolism by fatty acid amide hydrolase, thus increasing anandamide intracellular levels. ¹²⁴ PEA is also metabolized by N-acylethanolamine acid amidase to palmitic acid and ethanolamine. ¹²⁴ There are no known drug–drug interactions reported with PEA.

There is significant preclinical evidence that PEA may effectively treat CIPN and prevent its occurrence. One non-placebo controlled trial suggests that there are clinical benefits. Presently, a placebo-controlled randomized controlled study tests PEA 400 or 800 mg daily for 8 weeks versus placebo in patients with established CIPN. A similar trial in patients receiving oxaliplatin or paclitaxel as either an adjuvant or neoadjuvant treatment for their cancer should be considered.

Side effects

PEA has no known side effects.

Clonidine

Introduction

Clonidine is an alpha2 adrenoceptor agonist and an imidazoline2 receptor agonist, which is U.S. Federal Drug Administration approved for attention deficit hyperactivity disorder in children, Tourette’s syndrome, adjunctive therapy for cancer-related pain, and hypertension.^{163 –165} There is a growing body of literature that suggests that clonidine may be an effective analgesic for neuropathic pain.^{166 –169} There is extensive evidence that perioperative clonidine is an effective analgesic in children, is opioid-sparing, and is associated with reduced postoperative nausea and vomiting.^{170 –177} We will not review spinal clonidine, as it is a common practice in interventional pain management, but will limit discussions to parenteral, topical, oral, and transdermal clonidine, particularly for pain.

Mechanism of action

Clonidine binds to imidazoline receptors within the CNS and causes hypertension. It also has anti-arrhythmogenic activity and activates alpha2 adrenoceptors, causing sedation. ¹⁷⁸ Both receptors may be involved in analgesia.^{179 –181} Clonidine preferentially binds to alpha2 rather than alpha1 adrenoceptors (200–1), so sedation occurs at low doses, but as clonidine doses are increased, anxiety may occur due to binding to alpha1 receptors.^{182 –184}

Clonidine may reduce pain by several different mechanisms. Clonidine binds to nor adrenergic receptors descending in the dorsal lateral funiculus, which inhibits incoming sensory nociceptive neurotransmission at the level of the dorsal horn.^185,186 Within the intermediolateral column of the dorsal horn, there is a dense population of alpha2 adrenoceptors on myelinated Ac and unmyelinated C fibers which inhibit excitatory neurotransmission within the dorsal horn. ¹⁸⁷ Neurologic injury increases the expression of alpha2 adrenoceptors in the dorsal root ganglion sensory neurons, which are then targeted by clonidine. ¹⁸⁸ Depending on the subtype of alpha2 adrenoceptors, activation of these presynaptic receptors inhibits the release of substance P, calcitonin gene-related protein, and glutamate.^189,190 Clonidine inhibits nerve sprouting from neuropathic injury.^191,192

Clonidine activation at alpha2 adrenoceptors causes downstream activation of inhibitory G-proteins (Gi/Go), which inhibits cyclic adenosine monophosphate (AMP) production and hyperpolarizes neuron membranes, thus reducing allodynia.^{193 –195} In this way, clonidine may be synergistic with opioid analgesia. ¹⁹⁵ Clonidine also reduces the expression of the vanilloid receptor TRPV1, which is upregulated with neuropathic injury and contributes to hyperalgesia and allodynia. ¹⁹⁶ Finally, clonidine does appear to downmodulate neuroinflammatory responses to neural injury.^{197 –200}

Preclinical studies

There are preclinical neuropathic pain models which demonstrate synergistic analgesia between clonidine and opioids.^{201 –204} Synergy has also been reported with acetaminophen and N-methyl-d-aspartate receptor blockers.^{205 –207} One of the advantages of a clonidine/opioid combination is that clonidine does not potentiate the respiratory depression of opioids, unlike gabapentinoids.^208,209

There is preclinical evidence that clonidine reduces pain behaviors in animals with oxaliplatin and vincristine neuropathy.^{210 –212} CIPN pain behaviors induced in male Wistar rats by paclitaxel injections were significantly improved with clonidine. ²¹³ The benefits appeared to be related to increased descending noradrenergic activity at the spinal cord level. Preclinical studies suggest that clonidine may reduce CIPN associated with oxaliplatin and paclitaxel. Clinical studies are needed to confirm preclinical findings.

Clinical studies

Oral

Clonidine (0.1 mg oral) has improved low-dose gabapentin analgesia in diabetic individuals with painful neuropathy. ¹⁶⁶ Oral clonidine 0.1–0.2 mg by mouth has been compared to zolpidem in patients with chronic pain and secondary insomnia. Clonidine’s time to sleep onset was quicker (p = 0.001), and pain was significantly improved relative to zolpidem. Sleep quality was better, and there was no amnesia, confusion, or falls with clonidine. ²¹⁴

Transdermal

Transdermal clonidine has been used for diabetic neuropathy. A small underpowered crossover trial found that transdermal clonidine 0.3 mg/day was tolerable and reduced pain as a trend but not significantly so (−13%, 95% confidence interval −29% to +3%). ²¹⁵ The “trend” needs to be validated in a large, well-controlled trial. A second study using an enrichment enrollment design using the same dose and route found that clonidine reduced pain by 20% (95% confidence interval +4% to +35%) in a group of patients with diabetic neuropathic pain. ²¹⁶

Intravenous

Intravenous clonidine has been used in terminally ill patients with poorly controlled symptoms, in particular pain and agitation. One report initiated clonidine at 75 µg IV and titrated to response (maximum dose 1200 µg/day). ²¹⁷ A similar group of patients was initially treated with 75–150 µg intravenous in patients with refractory pain to opioids or refractory agitation to antipsychotics and benzodiazepine. Doses were adjusted to response. Of 115 patients treated, 85 responded. ²¹⁸

Clonidine as an adjuvant analgesic

Clonidine is an understudied adjuvant analgesic. Clonidine is versatile, with options for parenteral, topical, oral, and transdermal administration. There is evidence that clonidine improves opioid analgesia without adversely influencing respiratory function and may reduce opioid analgesic tolerance. Clonidine also reduces opioid withdrawal symptoms. A combination of analgesia and improved sleep without benzodiazepine side effects suggests that clonidine may be a preferred sleeping medication for those individuals with chronic pain in palliative medicine or on opioids.

Pharmacokinetics

Oral clonidine is highly bioavailable, with peak concentrations between 60 and 90 min. It is 30%–40% protein bound and has a volume of distribution of 3.2–5.6 L/kg. ²¹⁹ This reflects its lipophilicity and wide distribution. It rapidly crosses into the CNS. Less than 50% is inactivated in the liver. There are no known active metabolites. Between 40% and 60% of clonidine is excreted by the kidneys unchanged. Renal failure increases the half-life from 12–16 to 24 h. ²¹⁹

Adverse effects of clonidine

Clonidine’s side effects include drowsiness, hypotension, dry mouth, and sexual dysfunction. In comparison with oral clonidine, transdermal clonidine reduces the incidence and severity of such symptomatic side effects as dry mouth, drowsiness, and sexual dysfunction. Minor skin reactions occur at the application site of the transdermal patch with moderate frequency. Adherence to transdermal clonidine therapy is high, and patients commonly prefer it to oral therapy. ²²⁰

Conclusion

Haloperidol, miragabalin, PEA, and clonidine have unique mechanisms that may effectively reduce neuropathic pain. Combinations with standard adjuvants should be explored. In addition, haloperidol on clonidine may be opioid-sparing, improving analgesia and reducing opioid tolerance. The benefits of the commercially available medications, haloperidol, PEA, and clonidine, should be explored further in randomized trials.