A literature review of management for opioid-refractory neuropathic cancer pain: an update and future perspectives

Introduction

Pain is a symptom experienced by many cancer patients. Its prevalence is 30% at diagnosis and increases to 90% with progression (1,2). Pain in cancer patients is often classified as either nociceptive or neuropathic, though many cases are a mixture of both types. Among patients with this cancer-related pain, 33% have neuropathic pain (2). The definition of neuropathic pain by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) is “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system” (3).

Neuropathic pain has a variety of causes, including lesions of the peripheral nerves, brain, and spinal cord. Nerve damage from the tumor itself or treatments such as chemotherapy, radiation, or surgery can cause neuropathic pain in cancer patients.

However, as both the clinical characteristics and treatment of neuropathic cancer pain (NCP) differ from purely nociceptive pain, chronic neuropathic non-cancer pain and cancer treatment-related non-neoplastic neuropathic pain, such as chemotherapy-induced peripheral neuropathy (CIPN), we refer in this review to NCP as pain caused by a primary tumor or its metastases that damages or impairs the peripheral or central nervous system (4).

The direct effects of the tumor and the associated inflammation have always driven significant nociceptive mechanisms, which often explains the need to consider the mixed pathophysiology of nociception and neuropathy in many cases of NCP (5-8). It is also necessary to understand, in detail, the unique nature of NCP. Namely, the complexity and heterogeneity of the NCP symptom profile, including varying degrees of disease progression, comorbid clinical symptoms, and additional symptoms (including pain aggregation and the need for concurrent antitumor therapy), all contribute to making clinical trials challenging. In fact, the pathophysiology and pain of NCP patients are unstable, making long-term observation beyond a few weeks difficult and affecting the dosage and frequency of analgesic administration (9).

In addition, ethical concerns related to patient frailty and other characteristics require the precise selection of the most appropriate design and methodology that consider patients’ features. Existing treatment guidelines are based almost exclusively on many noncancer clinical trials (10) and do not consider vital issues like side effects and changes in kinetics of these agents in oncology patients (9). Furthermore, the neuropathic pathophysiology that contributes to an individual’s experience of pain is often unclear and not homogenously assessed according to each clinical practice (11).

In fact, according to nine European clinical practice guidelines (CPGs) on the diagnosis of neuropathic pain in cancer patients (12), a total of 149 references were used, of which 72 (48%) were related to cancer and 39 (26%) to neuropathic pain. Only 3 (2%) were related to neuropathic pain in cancer patients. Only 28 (19%) references were common to two or more guidelines. Only one shared reference was specific to cancer neuropathic pain. Recommendations and evidence ratings varied widely across guidelines. According to a systematic review of 30 studies on the medical management of neuropathic pain in patients with cancer (13), more than half of the studies were nonrandomized and the risk of bias was significant.

The inconsistency of treatment of NCP in different guidelines and the lack of high-quality research make this issue of great importance. In particular, the management of cancer patients with opioid-refractory NCP is a significant challenge.

For advanced cancer-related moderate or severe pain, opioid therapy is the first choice (14). However, in some cases, additional analgesic interventions may be considered (15). Notably, treating NCP with opioid analgesics alone has resulted in poorer outcomes (16), and the combination of opioid analgesics and adjuvant analgesics provides better analgesia (17). Patients with mixed neuropathic and nociceptive pain benefitted to the same degree as patients with neuropathic pain only (18). The adjunctive analgesics that are commonly prescribed for NCP are of the same type that are used for other non-cancer chronic neuropathic pain conditions (19).

Neuropathic pain requires multi-drug therapy, with adjuvant analgesics such as anticonvulsants and antidepressants added to opioids; however, strong evidence for their efficacy in NCP is limited (19). Numerous guidelines recommend gabapentinoids (pregabalin, gabapentin), selective serotonin noradrenalin reuptake inhibitors (SNRIs) such as duloxetine, and tricyclic antidepressants (TCAs) such as amitriptyline as first-line drugs with careful titration (9,19-23).

This narrative review aims to review the diagnosis process in detail and summarize the current options for treating opioid-refractory NCP and to highlight emerging promising therapeutic approaches. We present this article in accordance with the Narrative Review reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-23-175/rc).

Methods

A literature search was conducted through the PubMed database from 7 to 20 August 2023. The search language was limited to articles in English. We used terms “neuropathic cancer pain” or “cancer-related neuropathic pain”, and “management”. The authors’ agreement determined the selection of papers used. Primary literatures and systematic reviews are selected. Only high-quality studies were selected as secondary literatures. The search further prioritized articles published within the last 20 years but considered older articles separately. A total of 205 papers were reviewed, and 142 were finally included. Table 1 provides an overview of search methods.

General principles of opioid-refractory NCP management

When treating opioid-refractory NCP with adjuvant analgesics, the first important point to consider is the correct diagnosis of neuropathic pain for which adjuvant analgesics are effective. For example, in the case of breakthrough cancer pain (BTCP) (24), though it is a type of cancer pain and can occur as neuropathic pain, this pain can be treated by using rapid-onset opioids (ROO) as a first-line option. Also, opioids are generally not recommended by guidelines as a first-line treatment for neuropathic pain, and some evidence of efficacy is in the preclinical phase (25,26).

However, opioids may be marginally more effective in cases of neuropathic pain rather than neuralgia. Neuropathic pain of tumor origin is often mixed with a nociceptive pain component, making opioids an option. What is important is that opioids have little effect on neuralgia, but a little effect on neuropathic pain (27), so differentiation is important. Furthermore, it is worth noting that in the medical literature, neuralgia (other than trigeminal neuralgia) and neuropathic pain are often confused as if they are the same pain (28). For neuropathic pain, the location of the pain is generally patterned, so it is beneficial to remember the five most frequent patterns [brachial plexus involvement, intercostal nerve or chest wall involvement, nerve root involvement due to vertebral metastases (e.g., thoracolumbar metastases), pelvic plexus involvement, and facial nerve involvement (e.g., trigeminal nerve)]. NCP can be classified into specific cancer pain syndromes in details according to the type of neurologic involvement, including plexopathy, radiculopathy, and peripheral neuropathy, based on the association between pain characteristics and signs and symptoms of the underlying disease (29).

Next is the use of adjuvant analgesics. As the evidence of NCP is limited, they could be selected based on the evidence of non-cancer neuropathic pain, such as diabetic peripheral neuropathy and postherpetic neuralgia (30), and on an understanding of pain transmission pathways and the mechanisms of action of adjuvant analgesics. However, a previous study has shown that adjuvant analgesics are less efficacious in treating cancer pain than non-cancer pain (31). Furthermore, adjuvant analgesics have many side effects. It is important to remember that World Health Organization (WHO) guidelines (32) “recommend clinical trials” and to prescribe with the mindset of immediately reducing or discontinuing harmful dosages. At the same time, as adjuvant analgesics are adjunctive to opioids, one must ensure sufficient opioids are used.

It is vital to recognize that, in principle, the dosage of adjuvant analgesics can be increased up to the maximum after administration (33); however, in clinical practice, it is often impossible to increase the dose to the maximum due to side effects. At minimum, one should consider increasing dosage to the maximum allowable before judging them ineffective only based on the starting dosage. The most frequently used anticonvulsants and antidepressants are selected based on the following two points: In other words, (I) the intensity of the electric shock caused by NCP [i.e., repeated episodes (most often bursts) of excruciating sharp, lancinating pain, typified by neuralgic pain, or burning/searing and characteristically associated with allodynia, typified by typical neuropathic pain]; and (II) tolerable side effects that vary from patient to patient. If inhibition of a patient’s pain transmission pathway is not perfectively effective, an adjuvant analgesic that acts on another pathway should be selected for efficacity testing. Finally, switching to tapentadol and further investigating methadone as an adjuvant analgesic may aid in managing opioid-refractory NCP.

Evaluation of neuropathic pain

Screening tools

Screening questionnaires such as Douleur Neuropathique 4 Questions (DN4) (34), Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) (35), and the pain DETECT Questionnaire (PDQ) (36) have been developed for the identification of clinical features of neuropathic pain and have been used in cancer patients (6).

While these results alone should not be utilized to diagnose neuropathic pain, they are a valid screening tool and should be considered for proactive use. There is still no homogeneous and standardized method of combining the clinical diagnosis with the results of these screening questionnaires.

Diagnosis of neuropathic pain

Correct assessment of pain is essential for appropriate pain management (37). The diagnosis of NCP is not straightforward in most cases due to its heterogeneous nature, and, to date, there is yet to be a standardized gold standard for its evaluation (5). In 2008, NeuPSIG of the IASP developed a proposed diagnostic assessment algorithm to aid in the diagnosis of probable or definite neuropathic pain (38) (Figure 1, 2008 model).

Figure 1 Flow chart of grade system for neuropathic pain (2008 model).

The following four criteria are used in the grading system:

• Criterion 1: pain distribution is neuroanatomically plausible.
• Criterion 2: history suggests relevant lesion or disease.
• Criterion 3: pain is associated with sensory signs in the same neuroanatomically plausible distribution.
• Criterion 4: confirmation of the lesion by diagnostic testing.

Clinical points to consider include the following examples:

• Criterion 1: whether the site of pain corresponds to the dermatome of the nerve root or the area innervated by the peripheral nerve.
• Criterion 2: the presence or absence of subjective symptoms such as “shooting”, “electric-shock”, “prickling”, “tingling”, and systemic conditions such as diabetes.
• Criterion 3: the presence or absence of hypoesthesia to palpation at the site of pain.
• Criterion 4: imaging findings that may explain the neuropathy.

A probable diagnosis of neuropathic pain is indicated by criteria 1, 2, and 3 or criteria 1, 2, and 4. The presence of all four criteria provides a definitive diagnosis of neuropathic pain. However, in 2014, these criteria were revised to include patients with cancer, resulting in the proposal of the European Association for Palliative Care (EAPC)/IASP algorithm for diagnostic criteria for NCPs (39) (Figure 2, 2014 model).

Figure 2 Algorithm for the diagnosis of neuropathic pain in cancer patients with pain (2014 model).

In this 2014 model, a neuroanatomically plausible distribution of pain (step A) and clinical findings of neurologic damage (step B) lead to a clinical hypothesis of neuropathic pain. Interpretation of the available history and documentation (step C) requires determining (I) whether the history and documentation are sufficient and specific to attribute the cause of the pain to the tumor or the treatment of the tumor; and (II) whether the documentation demonstrates neurologic damage compatible with the clinical findings. If the history is consistent with a relevant neurologic lesion, a definitive diagnosis of neuropathic pain may be in order. Otherwise, further diagnostic testing is recommended (step D). These should be sufficient to confirm a specific etiologic lesion; if not, the condition is referred to as “probable neuropathic pain in a patient with cancer” (40).

More recently, in 2016, diagnoses were sometimes made using the new algorithm represented in Figure 3 (2016 model) (41). Diagnosing neuropathic pain requires evaluating the four factors listed in 2008 model as well as clinical considerations. In the algorithm represented in Figure 3, the presence of Criterion 1 and Criterion 2 means NCP is possible, adding Criterion 3 renders the diagnosis probable, and Criterion 4, definite (probable if Criterion 4 is recognized but Criterion 3 is not confirmed). In contrast, in the algorithm represented in Figure 1, the presence of both Criterion 1 and Criterion 2 results in a “Possible” diagnosis, adding either Criterion 3 or Criterion 4 results in a “Probable”, and both are “Definite”. Therefore, Criterion 3 and Criterion 4 are extremely important for diagnosis. Note that previous studies have pointed out many shortcomings in the evaluation of Criteria 1 and 4, in particular (41).

Figure 3 Flow chart of updated grading system for neuropathic pain (2016 model).

Recently, Diagnostic workup using the Italian Society of General Medicine (SIMG) method version 3.0 (42) has also been proposed. These are easily performed by combining the results of six observations/tests:

• Outline the affected area with a marking pen to identify the main pain zones.
• Are there any specific factors in the painful area (e.g., corresponding to plexus, root, or nerve)?
• Are there any signs of somatosensory system deficiency?
• Are there any signs of receptor sensitization (primary allodynia)?
• Are there any signs of spinal sensitization (secondary allodynia)?
• Are there any inconsistencies?

Armed with the results of these simple questions and a thorough medical history to assess psychological stress, an algorithm can be used to identify pain.

When the cancer causes a neurologic lesion, and the pain refers to the site of the neurologic lesion of interest, a diagnosis of a neuropathic component in the pathophysiology of the pain should be made. Negative neurologic signs and decreased motor function may confirm the presence of neurologic dysfunction, but pain may or may not be accompanied by positive neurologic signs of increased neural excitability, such as allodynia and hyperalgesia, which are typical symptoms of neuropathic pain. Occasionally, other symptoms such as dysesthesia, paresthesia, and burning sensations may be present, which are considered characteristic of NCP.

Selection of adjuvant analgesics by pathological condition

Brachial plexus involvement, intercostal nerve or chest wall involvement, thoracolumbar spine metastasis (nerve root involvement), pelvic plexus involvement, and nerve involvement of the face (e.g., trigeminal neuralgia) are typical examples of pain. Different drugs may, therefore, be more efficacious when applied to the correct type of NCP. Anticonvulsants such as pregabalin, for example, are appropriate for electrical pain described as “shooting” or “electric shock”, and carbamazepine is more appropriate for trigeminal neuralgia. Antidepressants are appropriate for less electrifying pain, such as “prickling” or “tingling” (43).

When combining adjuvant analgesics, we recommend the use of drugs with different mechanisms of action considering the pathophysiology (44). Examples include calcium channel antagonists (e.g., pregabalin, gabapentin) for peripheral sensitization or when multiple factors are suspected (also effective for central sensitization and nerve root symptoms), sodium channel antagonists (e.g., carbamazepine, lidocaine, valproic acid) for suppression of the ectopic firing of nerve fibers and nerve roots (sometimes with more intense electric shock pain), and N-methyl-d-aspartate (NMDA) receptor antagonists (e.g., ketamine, methadone) may be selected if suppression of central sensitization is expected.

Although good results have often been obtained when two or more drugs including opioids are used together, specific combinations are not recommended due to the small number of clinical studies (20,45-47).

Typical pharmacological management of opioid-refractory NCP (adjuvant analgesics)

Anticonvulsants such as gabapentinoids, antidepressants such as SNRIs, and TCAs are generally effective in managing neuropathic pain (48). Although data on the efficacy of these agents in NCP patients are lacking, they remain among the primary agents used in these populations (49,50).

We generally administer these agents with non-opioid and opioid analgesics for NCP (50). Due to the diversity of patients and pain symptoms, high-quality evidence is lacking to support the use of specific agents for NCP. We have updated frequently used candidates for pharmacological management of opioid-refractory NCP in Table 2. As the starting and maximum doses differ depending on each region, we have updated the neuropathic pain guidelines for each country and area.

Anticonvulsants

Neuronal hyperexcitability plays an essential role in the pathophysiology of neuropathic pain. According to the systematic review conducted by Jongen et al. in 2013 (18), the absolute risk-benefit (ARB) and the absolute risk-harm (ARH) of anticonvulsants for NCP were 0.567 and 0.050, respectively. Some reports suggest that number needed to treat (NNT) values have little practical significance due to the heterogeneity of various neuropathic pain types (20,51).

Gabapentinoids (pregabalin, gabapentin, mirogabalin)

Bind to the α2δ subunit of voltage-gated Ca²⁺ channels in the spinal cord dorsal horn (52). They inhibit Ca influx at the presynapse, necessary for the release of pain-informing neurotransmitters.

Gabapentinoids have been widely used in the treatment of neuropathic pain because they reduce pain transmission in spinal pathways and modulate central descending inhibitory pathways (53). Although only pregabalin and gabapentin have evidence in randomized clinical trials (RCTs) for NCP, and are the two drugs most frequently used to treat this condition, in actual clinical practice, we also use mirogabalin. Both of the tested drugs have established efficacy for neuropathic pain, and EAPC recommendations and the European Society for Medical Oncology (ESMO) CPGs recommend them as first-line agents for NCP (14,51). Somnolence and dizziness are the most common dose-limiting reactions, sometimes with edema.

As mentioned, several RCTs have demonstrated the efficacy of these agents in NCP (54-56), but further efficacy and safety data are needed in NCP patients (57). Gabapentinoids may have a strong image as an analgesic that can be prescribed long-term, but extensive study has also shown an association with suicide, overmedication, and traffic accidents (58). Although quality evidence in cancer patients is lacking, it may also be associated with indications for anxiety and should be discontinued in cases of ineffectiveness.

Pregabalin

There is evidence of efficacy in neuropathic pain, and it is often the first choice, with NNT of about eight (45). RCTs have shown benefits in patients with cancer pain (59-61), but evidence for NCP is limited to only one RCT (54). An open-label randomized study has investigated the use of pregabalin over fentanyl in patients with moderate-to-severe NCP, showing some benefits and suggesting that pregabalin monotherapy in NCP may lead to better control of the neuropathic component, with opioid-sparing effects (62).

In patients with impaired renal function, the dosage should be reduced (and supplemented immediately after dialysis, as it is removed by dialysis). Side effects include drowsiness, lightheadedness, dizziness, and edema, and it is safe to start with smaller doses for aged people and patients with impaired general function. Although analgesic effects are more likely to be obtained with increased dosages of adjuvant analgesics, studies of patients in a palliative setting have shown that it is often difficult to increase the dose to 300 mg/day or more (63,64).

Gabapentin

There is evidence of efficacy in neuropathic pain. It is often the first choice, with an NNT of about seven (49). Two high-quality RCTs have shown the usefulness of gabapentin in cancer patients (56,57), and though it is often possible to increase the dose to 1,800 mg/day, a dose reduction is necessary for renal impairment. The side effects of gabapentin are like those of pregabalin except less somnolence. One report suggests that a linear conversion to pregabalin is undesirable because the oral bioavailability of gabapentin is dose-dependent. In contrast, the oral bioavailability of pregabalin is dose-independent, so the conversion is not exact (65). However, it is sometimes converted to pregabalin at about 1:6 (300 mg of pregabalin = 1,800 mg of gabapentin) (66). One study showed the association between myoclonus and the use of gabapentin (67).

Mirogabalin

RCTs have shown efficacy in non-cancer neuropathic pain, such as diabetic peripheral neuropathy (68) and postherpetic neuralgia (69), but there are no high-quality RCTs in cancer patients. Dose reduction is required in renal impairment, and side effects are like pregabalin but may be less severe. It is said to have a conversion ratio of about 17:1 to pregabalin (70); however, it is sometimes converted at about 15:1 (300 mg of pregabalin = 20 mg of mirogabalin). Note that the potency of the maximum dose of mirogabalin (30 mg) is lower than that of the maximum dose of pregabalin.

Other anticonvulsants

Other antiepileptics, including lamotrigine and carbamazepine, are less commonly used for NCP (71-74). Carbamazepine is effective in non-cancer patients with trigeminal neuralgia, postherpetic neuralgia, and diabetic neuropathy (73). However, its side effects, such as myelosuppression and skin rash, can sometimes be severe. It is contraindicated in severe cardiac disorders (atrioventricular block of degree II or higher, severe bradycardia) due to its adverse effects, such as conduction depression. It is unlikely to be used in cancer patients who take multiple drugs because of its induction of CYP3A4. However, it may be considered for refractory facial neuropathic pain (e.g., trigeminal neuralgia).

Antidepressants (e.g., duloxetine, amitriptyline)

An analgesic effect is observed independently of the mood-modifying effects (75), and they exert this effect by enhancing the descending inhibitory pathways, increasing supraspinal and spinal norepinephrine and serotonin release at the synaptic cleft (76).

The onset of effect is faster than that of antidepressant action, and in some cases, it is effective even at low doses. A review article based on five RCTs, three of them with amitriptyline, estimated an ARB of 0.551 and an ARH of 0.126 (18).

SNRIs

SNRIs, mainly duloxetine, have been studied and recommended to manage CIPN (77,78). However, some recent studies have shown that adding duloxetine to opioid or opioid-pregabalin therapy may benefit patients with refractory NCP (79,80). Common side effects of SNRIs include somnolence, dry mouth, dizziness, and increased sweating.

Duloxetine

There is evidence that duloxetine is effective for neuropathic pain, and the NNT is around six and so the drug is often the first choice (48). It is effective against chemotherapy-induced neuropathic pain caused by anticancer agents (particularly platinum drugs) (78). There might be a clinical benefit (NNT is 3.4) in alleviating refractory NCP (81), and the drug may be particularly effective for tingling pain (43). The addition of low-dose duloxetine (20–40 mg/day) to opioid-pregabalin combination therapy in this multicenter, randomized, placebo-controlled trial conducted in 12 specialized palliative care units in Japan (81) provides further evidence. In addition, a recent study has shown that combination therapy with opioids (especially methadone) and duloxetine is more effective than either alone (79). Furthermore, a recent randomized study has shown that duloxetine effectively treats neuropathic pain in lung cancer patients (82).

However, there are gastrointestinal symptoms (e.g., nausea, anorexia) in the early stages of duloxetine administration, antiemetics may be used concomitantly, and as there is a risk of decreased appetite, caution should be exercised when using duloxetine, especially in patients in poor condition. Other side effects include somnolence, urinary retention, constipation, dizziness, and serotonin syndrome with concomitant use of monoamine oxidase inhibitors, other antidepressants, and some kinds of opioids (e.g., tramadol, tapentadol) (83).

Venlafaxine

Venlafaxine has not been widely used for NCP due to the lack of studies. Its effect on NCP is not as straightforward as that of duloxetine, which had better results in CIPN (84).

TCAs

There is evidence of efficacy in both cancer and non-cancer, with an NNT of about 4, and they are often the first choice (48). RCTs have shown their usefulness in cancer patients (54,85,86), but they also have many side effects. Side effects include anticholinergic effects, often resulting in dry mouth, dysuria, and constipation. Patients with severely impaired general condition and the elderly are prone to drowsiness, delirium, and disorientation. Drug toxicity such as anticholinergic effects may be dose limiting for TCAs.

Paroxetine

According to a recent article, paroxetine may enhance analgesia and reduce side effects by targeting peripheral delta opioid receptors (DORs) (87). For those who are highly compulsive (e.g., “I want my pain to be zero” or have a history of chronic pain or other problems before cancer treatment), paroxetine, the only selective serotonin reuptake inhibitor (SSRI) that also has noradrenaline reuptake effects, may be used with caution of activation syndrome which sometimes leads to suicide.

Corticosteroids (dexamethasone, betamethasone)

The main mechanisms of action are anti-inflammatory and anti-edema, and we often see cases where they are more effective than other adjuvant analgesics, but in cancer patients, there have been conflicting reports, and the jury is still out on their effectiveness (88,89). The highest level of evidence is only for spinal cord compression symptoms with numbness, muscle weakness, and vesica-rectal disturbances (90), but they can also be effective in conditions such as neuropathic pain due to plexus invasion of tumors, increased intracranial pressure in the brain, bone metastasis pain with poor response to non-opioid or opioid analgesics, pain flare-ups after the initiation of radiation, malignant gastrointestinal obstruction for which invasive treatment is not possible, and cancerous pleurisy or peritonitis. The level of evidence for other analgesic adjuncts is similarly low (19,50), so aggressively consider the possibility of adding corticosteroids, especially if the prognosis is less than a couple of months. Assessment should be continued for approximately one week after administration or titration, and if ineffective, the drug should be discontinued.

Steroids exceeding 40 mg/day of prednisolone equivalent are associated with developing psychiatric symptoms such as anxiety and agitation (91). A tapering regimen starting with a higher dose (4 to 8 mg/day, followed by maintenance at 0.5 to 4 mg/day) is often used for more emergent pain. On the other hand, we usually take a titrating regimen starting with a lower dose (0.5 to 2 mg/day, followed by maintenance at 0.5 to 4 mg/day) for less emergent pain. Because of steroids’ long-acting nature, they should be administered once in the morning (or twice in the morning and afternoon) to avoid insomnia and delirium.

Other pharmacological management of opioid-refractory NCP (adjuvant analgesics)

As there is no strong evidence for the administration of adjuvant analgesics, we must be careful to use them sparingly, but they may be effective in certain conditions.

Lidocaine

Lidocaine acts on Na⁺ channels and stabilizes neuronal cell membranes, suppressing excitability and producing analgesia. While there have been RCTs in cancer patients, it is not a first-line drug concerning efficacy and side effects and could be given when other drugs do not work. In addition to continuous intravenous and subcutaneous injections, 2–5 mg/kg can be dissolved in a saline solution and administered dropwise over 30 minutes (92). There have also been reports of the efficacy of a 10% lidocaine ointment preparation for allodynia (93).

A prospective, non-randomized, open-label study showed that the addition of a 5% lidocaine patch was beneficial in the short-term treatment of neuropathic pain associated with allodynia, regardless of the type of pain, in patients with post-thoracotomy and post-mastectomy pain or chest wall tumor pain. Lidocaine has minimal systemic absorption. In patients receiving class I antiarrhythmic drugs, however, it should not be used (71).

Drowsiness is common but mostly not severe (94), and side effects include (severe) bradycardia, hypotension, and symptoms of lidocaine toxicity such as numbness of the lips and central nervous system symptoms (drowsiness, convulsions, anxiety, agitation, and tremor). Use of the drug is contraindicated in patients with severe conduction abnormalities. A history of local anesthetic allergy, cardiac disease (especially bradycardia), cardiac arrest, and an electrocardiogram should be obtained before use.

Ketamine

Ketamine is a potent antagonist of NMDA receptors on spinal dorsal horn neurons. Although there have been reports of its efficacy in cancer patients, the results have been conflicting, and the evidence for its efficacy as an analgesic is not strong (95,96). Ketamine is less well tolerated than the other antagonists because of an increased incidence of side effects, such as psychiatric symptoms [e.g., nightmares, delirium, hallucinations, drowsiness, abnormal sensations, and a dissociative mental state (97)], headache, nausea, dizziness, and increased blood pressure. It has contraindications in patients with cerebral hypertension. Although it cannot be recommended for routine administration (50), there are no clinical trials for neuropathic pain involving central sensitization (98), and there is insufficient evidence to evaluate benefits and harm (99). Despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain (100). It is not a first-line drug in terms of efficacy or side effects. It may be effective when other drugs are ineffective (e.g., for refractory neuropathic pain or recovery of opioid analgesic tolerance).

Valproic acid

Valproic acid has diverse mechanisms of action, including promoting gamma amino butyric acid (GABA) neurotransmission in the brain and inhibiting voltage-gated Na⁺ channels. Efficacy has been demonstrated in small comparative studies for cancer (101). For patients with comorbid bipolar disorder, a dose of 800–1,200 mg/day of valproic acid given once or twice daily may have a dramatic effect. It should be used cautiously in cases of hepatic impairment and hyperammonemia because of its relatively low sedative effect, which can be problematic with general adjuvant analgesics.

Baclofen

Baclofen binds to and activates GABA-B receptors and decreases the release of excitatory amino acids by lowering Ca concentrations. A small observational study in cancer patients (102,103) has been of empirical use. Baclofen is an option for treating malignant iliopsoas syndrome, especially in combination with diazepam, but should be tapered because of the potential for withdrawal symptoms (e.g., delirium, seizures) if abruptly discontinued. Dose reduction should be considered in the presence of renal impairment. Side effects include drowsiness, gastrointestinal symptoms, impaired consciousness, and respiratory depression.

Other pharmacological management of opioid-refractory NCP (clonazepam, capsaicin, and Kampo medicine)

Clonazepam

Clonazepam is a drug that exerts its analgesic effect by binding to GABA-A receptors and increasing GABA neurotransmission. Its use is often empirical, although there has been one small observational study in cancer patients (104). Clonazepam, by its nature as a benzodiazepine anticonvulsant, is likely to be highly effective when used preferentially in people who complain of insomnia or have high anxiety. It also has the advantage of anxiolytic properties and the possibility of dose adjustment every few days. However, it should be administered with particular attention to drowsiness and delirium because of its relatively long half-life (approximately 4–5 days).

Capsaicin

There are recommendations for non-cancer pain, mainly for local neuropathic pain such as postherpetic neuralgia (105). On the other hand, in cancer patients, there is only one RCT (106) suffering from neuropathic pain after cancer surgery (i.e., non-cancer pain), and no high-quality studies on tumor-related NCP. Capsaicin has ‘unexplored’ therapeutic potentials that are not considered by the guidelines due to a lack of robust evidence.

Kampo medicine

Kampo Medicine, mainly goshajinkigan, have been studied for prevention of CIPN (107). However, recent meta-analysis (108) has shown that use of goshajinkigan as standard care for prevention of CIPN is not currently recommended. There has also been no study for NCP. Kampo Medicine has ‘unexplored’ therapeutic potentials that are not considered by the guidelines due to a lack of robust evidence.

Opioid switching

When one opioid is ineffective or specific side effects appear, switching to another opioid (opioid switching) may improve efficacy (109). The effectiveness of opioids may vary by approximately 15 times between individuals (110), and switching to opioids that act on the noradrenergic system may be particularly effective.

Tapentadol, a dual opioid receptor agonist and norepinephrine reuptake inhibitor, has also been suggested for NCP, particularly in cases where immediate dose adjustment is needed or in patients at high risk for side effects (111,112).

Tramadol is also used to treat neuropathic pain because it affects µ-opioid receptors and inhibits serotonin and noradrenaline reuptake (113). A double-blinded, placebo-controlled trial in patients with NCP showed that tramadol was significantly more effective than a placebo for improvement in pain intensity and quality of life and reduction in antiepileptic analgesic use (114). However, it is not known whether tramadol works in opioid-refractory NCP. Serious side effects or poor opioid efficacy may require a change in opioid type or route of administration, which is also true for NCP patients.

Opioid switching (115)—substituting one opioid for another enhances opioid responsiveness (109). It has been reported that approximately 50% to 90% of patients achieve satisfactory pain control and reduced side effects after opioid switching (116). Methadone (which has the great advantage of being very inexpensive), has been shown to be effective in pain relief and reduction of opioid toxicity, especially in patients treated with other opioids at high doses and in the presence of NCP (117).

Methadone as an adjuvant analgesic

In addition to moderate and severe cancer pain, NCP and neuropathic pain from other chronic non-malignant diseases are treated with opioid analgesics (118). In a report published in 2020 by Fürst et al. (survey of methadone use in 410 patients), adding low-dose methadone to prior opioids for the treatment of intractable pain (many of them are NCP) in advanced cancer may be a valid approach (119). In this study, methadone was administered at a low dose added to the pre-existing opioid. However, the dosage of the preceding opioid at the start of methadone was high, with a median of 184 mg/day and a mean of 456 mg/day for oral morphine. In addition, even when the dose of the preceding opioid was low (90 mg/day equivalent to oral morphine or less), adding methadone (5 mg/day as a starting dosage, and after confirming no QTc prolongation and no side effects after 1 week from the initiation, increased to 10 mg/day) could be effective.

Low-dose methadone add-on therapy as an adjuvant analgesic may function without worsening pain control because it is added to the previous opioid and adjuvant analgesics maintained at the same dose. Methadone 10 mg/day is below the minimum dosage for methadone described in the appropriate use guide, indicating the potential for pain control with lower doses of methadone in combination with prior opioids. A cochrane review in 2017 (120) also stated that low-dose methadone therapy as an analgesic adjuvant is a potential treatment that deserves consideration.

On the other hand, methadone’s potential as a first-line opioid is negative, mainly due to difficulties with dose escalation and the risk of drug-drug interactions and severe side effects. Furthermore, Ehret et al. (121) reported that QT prolongation, which can cause fatal arrhythmias, was dose-dependent, suggesting that low-dose methadone add-on therapy as an adjuvant analgesic is associated with fewer side effects. Therefore, if it is possible to perform regular electrocardiogram examinations and confirm electrolytes, it may be possible to initiate low-dose methadone therapy at home while reducing the risk, and the range of future applications will be broad (122).

Cannabis and promising novel therapeutic agents

Cannabis is generally considered to be an alternative to conventional treatment when patients are non-responders or have severe side effects. A potential analgesic role for cannabinoids has been suggested by preclinical data in NCP models (123,124). However, the addition of cannabinoids to opioids did not reduce cancer pain, according to a recent systematic review and meta-analysis of the effects of cannabinoids on cancer-related pain and adverse effects compared with placebo or other agents (125).

Cannabinoids’ effectiveness is still unclear (126).

The pathophysiology and neurobiology of pain are now well understood. Tetrodotoxin, botulinum toxin type A (BoNT-A), the transient receptor potential (TRP) M8 activator menthol, growth factor inhibitors (29), and highly selective inhibitors of NaV1.8 (127), are among the agents recently introduced into clinical practice or currently under investigation.

Spinal cord stimulation (SCS)

The gate control theory of pain was the starting point of the development of SCS (128). Few studies have been conducted on SCS in patients with neuropathic pain secondary to tumors (129,130). A literature review identified several series, but no RCTs. A total of 92 patients with neuropathic pain secondary to the tumor were analyzed and showed a clear reduction in pain (131).

Gene polymorphism and other biomarker candidates

Genes studied for association with opioid clinical efficacy and adverse events include opioid mu receptor (OPRM1), catechol-O-methyltransferase (COMT), and CYP2D6 (132,133).

According to a recent review in 2017 (132) and guidelines based on a systematic review in 2021 (133), there is limited evidence for an association between OPRM1 polymorphism A118G (rs1799971) and analgesia or opioid dosage or adverse events, and COMT rs4680 genotype or CYP2D6 genotype (particularly CYP2D6*10. allele/C188T) as well. However, another recent evidence-based study has shown that if patients have an OPRM1 G/G genotype or COMT GG genotype, clinicians need to consider initiating morphine at a higher dose and providing for more aggressive dose titration (recommendation grade B) (134). Poor metabolizers of CYP2D6 may be at risk of treatment failure due to the inability to convert the parent drug into its more active metabolite, and ultra‑rapid metabolizers are at risk of treatment‑related toxicities. Another study recently conducted by Fujita et al. has shown that oxycodone tended to be superior to morphine in patients with genotype AA for the CCL11 (eotaxin) rs17809012 SNP (135), suggesting it may serve as a potential biomarker for personalized analgesic therapy in cancer pain patients.

A recent prospective study showed that, due to their dual mechanism of action and low sensitivity to the OPRM1 A118G polymorphism, tapentadol and methadone might be better choices for G-allele carriers than hydromorphone, oxycodone, and fentanyl (136).

Unfortunately, there is no high-quality research on the genetic approaches currently available; however, a new era that reviews the features of baseline opioids for personalized medicine is approaching.

Discussion

The management of opioid-refractory NCP remains a significant challenge. In this review, defining NCP as pain due to nerve tissue damage caused by tumor or metastasis, we aimed to summarize current treatment options for NCP and highlight promising new therapies. The first important consideration when managing opioid-resistant NCP is the accurate diagnosis of neuropathic pain, followed by adjunctive analgesics. Adjunctive analgesics are selected based on evidence for non-cancer neuropathic pain but may be less effective for NCP than for non-cancer pain. The pharmacological management that has most definitely been described as adjuvant analgesics for opioid-refractory NCP is anticonvulsants and antidepressants, and it is essential to use them selectively by the nature of NCP and side effects permitting each patient.

Several limitations need to be discussed.

First, the NCP has heterogeneous symptoms and a lack of evidence-based treatment.

To address the heterogeneous causes of NCP, we excluded patients with CIPN and central neuropathic pain and focused on patients with tumor-derived NCP. However, we still combined various peripheral NCPs. Therefore, we warned that there is a need to be especially aware of the differences between NCPs (e.g., between neuralgia and neuropathic pain) and that most previous studies have confused them (28). Furthermore, the limitation of Table 2 is that they have unknown applicability to populations with severe chronic diseases like cancer. Also, as none discusses corticosteroids, considered essential analgesics for NCP with advanced stages, we have added the discussion.

Second, there might be needs to be more devotion to “dose titration” methods in clinical trials, which is essential for all the drugs discussed. We believe that, in comparison studies of active interventions such as drug A vs drug B, if the interventions tested are to “adjust individually the dose to decrease pain intensity and keep side effects within a certain range”, and the endpoint is also “pain symptoms and adverse events”, it would be a natural result that there is no difference between the drugs. We should be extra cautious about RCTs with dose adjustment where the endpoint is included within treatment protocol such as dose adjustment. Regardless of whether the patient is in pain or not, it may be recommended to try to increase the dose of adjuvant analgesics up to the maximum dose (unless there is an adverse event) (33), which would make it easier to understand the efficacy of the drug, although it might not be practical in clinical practice. Unlike in the non-oncology setting, virtually no drugs meet the IMMPACT recommendation (137) of ≥ NRS2 or ≥30% reduction from baseline pain intensity, meaning moderate improvement in responder analysis in cancer patients, and the WHO guideline (32) has recommended clinical trials be conducted.

Finally, we have not discussed opioid tolerance and assessing the presence of depression (138) in this review, both of which are strongly associated with pain. True pharmacologic tolerance itself is highly complex and involves several mechanisms, including upregulation of opioid metabolism, desensitization of receptor signaling, and receptor downregulation (139). These mechanisms are induced by drug administration and may be related to concurrent opioid-induced hyperalgesia (OIH), although the two processes are distinct in clinical practice (139,140). If the loss of analgesic efficacy is due to the development of tolerance (or disease progression), increasing the opioid dose may manage the pain; conversely, if the loss of efficacy is due to OIH, increasing the dose may exacerbate the pain. It is also important to assess for the presence of depression. In cancer patients, medical professionals tend to overlook depression (141) (because the symptoms of cancer and cancer treatment, such as fatigue and loss of appetite, overlap with the symptoms of depression), leading to worsening of pain.

Conclusions

Many challenges remain in the management of NCP. Current guidelines for NCP treatment are based on limited evidence for non-cancer neuropathic pain and are often contradictory for cancer patients. More robust RCTs are needed to provide strong evidence for existing recommendations in the future.

As good research follows from good clinical practice and appropriate pain assessment, it is essential that we identify a gold standard for the diagnosis of NCP. Preclinical research to discover new mechanisms and agents is also needed.

In the field of opioid-refractory NCP, many clinical questions remain, such as the optimal dose of opioids to start adjuvant analgesics, the optimal starting dose of each agent (from a risk-benefit perspective), the optimal drugs according to pathophysiology, and whether there is a difference in optimal adjuvant analgesics between NCP and non-painful numbness. As opioid-refractory NCP is a complex symptom, better knowledge of mechanisms and targeted therapeutics is needed.

Acknowledgments

Funding: This work was supported by Japan Agency for Medical Research and Development (AMED) Award in Innovative Clinical Cancer Research (No. 23ck0106850h0001).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-23-175/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-23-175/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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