MANAGEMENT OF NEUROPATHIC PAIN IN CANCER SURVIVORS

MANAGEMENT OF NEUROPATHIC PAIN IN CANCER SURVIVORS

Athina Vadalouca, Efklidis Raptis, Eleni Moka, Panayota Sykioti

Pain Relief and Palliative Care Center

Aretaieion Hospital, University of Athens, Athens, Greece

 

Pain is prevalent in patients with cancer and considerably undermines their quality of life, thereby making the development of a comprehensive pain management approach essential.

Neuropathic pain (NP) is commonly encountered in cancer patients and is considered a well-established entity for more than 20 years. Approximately, 1/3 of cancer patients experience NP, usually mixed with nociceptive components, but, also, as a single, autonomous entity. As advances in cancer identification/therapy prolong life expectancy, physicians’ efforts target in quality of life improvisation Cancer pain usually results from mixed mechanisms. An absolute distinction between cancer and non-cancer related NP is perhaps artificial. NCP pathophysiology basically remains similar to non-cancer NP, with common cross-referencing between the two conditions. Research on NCP determined distinct differences in the signature of neuroreceptors/transmitters’ alterations, unique damage and interruption of neuronal function and may yet elucidate pain induction or maintenance differences. NCP possesses unique characteristics and exhibits an incomparable molecular signature. However, therapy similarities to non-cancer related neuropathies, may explain the ability of drugs (e.g. gabapentinoids) in treating cancer pain, indicating possible neuropathic components

Metastatic spread of cancer to bone is one of the most important causes of NCP and painful muscle spasm, whereas breakthrough pain (defined as transitory flare of pain occurring on a background of relatively well-controlled baseline pain) may be prevalent, due to numerous aetiological factors (bone metastases, triggering pain on movement). Infiltration and injury of sensory neurons that innervate the bone marrow cause pain. Alterations in normal bone turn over occur, with loss of mechanisms that normally regulate the balance between osteoclast and osteoblast activity. With advanced disease, the bone loses mechanical strength and is subject to osteolysis, pathological fracture, and microfractures. Mechanical distortion of the periosteum may be a major source of pain.

NCP can also arise as a consequence of cancer-directed therapy, such as surgery, radiotherapy and chemotherapy (treatment-related therapy). Treatment adverse effects include joint pain following chemotherapy and hormonal therapy or/and painful mucositis due to radiotherapy and chemotherapy with certain agents. Drugs such as paclitaxel, vincristine, cisplatin and bortezomib have been widely reported to produce sensory neuropathies. Radiotherapy can induce injury, leading to microvascular insufficiency and fibrotic changes (radiation-induced fibrosis), affecting peripheral nerves and perineural tissues (e.g. brachial plexus fibrosis) and causing chronic NP that begins months to years following treatment. Chemotherapy induced NP(CINP) has been widely reported in controlled and uncontrolled studies. On one hand, more patients experience the excellent outcomes of chemotherapy, with prolonged survival. On the other hand, increasing numbers of patients are unable to complete full treatment because of CIPN development. Long-term pain management is therefore a challenging treatment aspect for neurologists, oncologists and pain specialists.

CIPN incidence is rising due to increased number of neurotoxic agents and because patients live longer, receiving multiple chemotherapy drugs. CIPN symptoms are often under-recognized, in part because of difficulties in diagnosis, in addition to patients’ underreporting. CIPN is documented frequently with vincristine, taxanes and platinum-based agents.

New approaches are desperately demanding in controlling cancer pain. Neuropathic Cancer Pain (NCP) frequently becomes severe as disease advances, requiring miscellaneous types of analgesics, at different time-points. The intrinsic difficulties in performing randomized controlled trials in cancer pain have traditionally justified the acceptance of drugs already known to be effective in benign neuropathic pain for the management of malignancy-related neuropathic pain despite the lack of relevant high quality data. Review of available literature reveals that the management of neuropathic cancer pain has changed dramatically in the past few years thanks to the improved perception of the problem, new therapeutic approaches and novel drugs. Current therapeutic strategies depend on pharmacotherapy, mainly with the inclusion of adjuvants. At present, variable agents are used to treat NCP, but despite the advances in pathophysiology understanding, management is still suboptimal. Intractable NCP remains an important epidemiological, clinical and economical burden worldwide, posing significant societal impacts.

Specific guidelines on the pharmacological treatment of NCP have been suggested by the European Federation of Neurological Societies (EFNS) Task Force. This Task Force concluded that there is a level A of evidence for the efficacy of gabapentin (one study), a level B for TCAs and tramadol and inefficacy of valproate.

In the following pages, non-opioid and opioid drugs that are recommended by the WHO for cancer pain therapy, as well as various classes of adjuvant analgesic drugs for NCP treatment will be presented.

Non-Opioid Analgesic Drugs

Non-opioids, such as NSAIDs , acetaminophen and COX-2 inhibitors, have limited usefulness in the management of NCP However, some patients do report relief, so a trial may be indicated. Many patients have concomitant neuropathic and nociceptive pain, which may respond to non-opioids.

Opioid Analgesics

The role of opioids has been re-evaluated during NCP therapy. Controlled-release oxycodone has been applied, because it is safe, well-tolerated and effective, although it is unlikely that opioids will replace antidepressants and antiepileptic drugs for NCP therapy. However, co-administration of oxycodone and paracetamol resulted in a low-dose synergic combination in different pain types. It has been reported that such a combination can be useful in cancer-related pain, including those situations that are complicated by a neuropathic component.

Morphine combined with gabapentin achieved better analgesia, at lower doses of each drug, than either as a single agent, with constipation, sedation and dry mouth as the most frequent adverse effects.

Clinically, opioids provide effective relief of cancer pain, although occasionally high doses must be administered, to suppress “breakthrough” pain or pain from nerve involvement. The most common adverse effects of opioids are constipation, sedation, drowsiness and nausea.

Recently, according to a systematic review of 35 years, conducted by WHO (2005), due to its favourable analgesic properties and low cost, methadone has been recognized as an important player in the treatment of both nociceptive and neuropathic pain and has been characterized as an essential analgesic in cancer pain management.

Tramadol Hydrochloride

Tramadol is a norepinephrine and serotonin reuptake inhibitor (SNRI), centrally-acting analgesic, which has direct, but weak opioid action (metabolite with major µ-opioid agonist effect) and indirect monoaminergic action (like TCAs). It is also devoid of immunosuppressive activity. RCTs have yielded positive results from tramadol and tramadol/acetaminophen combination in PDN , PHN and various NP states. In all trials, tramadol, titrated to a maximum dosage of 400 mgr/day significantly relieved pain, compared with placebo. Its beneficial effects on allodynia and quality of life are also reported.

The most frequent side-effects of tramadol include dizziness, nausea, constipation, somnolence and orthostatic hypotension.

Adjuvant Drugs (Adjuvants)

The widely-used adjuvants represent a major aspect in our NCP armamentarium. These include gabapentinoids (gabapentin, pregabalin), AEDs, antidepressants (TCAs, duloxetine, venlafaxine), corticosteroids,capsaisine 8% patch, biphosphonates, NMDA-antagonists, canabinoids and other substances

An adjuvant analgesic is an agent, whose primary indication is other than pain, exerting analgesic effects in certain painful conditions Not only are adjuvants important per se, but they also hold opioid-sparing effects.

Tricyclic Antidepressants (TCAs)

TCAs inhibit norephinephrine and serotonin reuptake, followed by augmentation of biogenic amines’ activity. Their action includes sodium channels’ modulation in the periphery and NMDA antagonism. As a result, TCAs enhance dorsal root inhibition and reduce peripheral sensitization.

TCAs are started with a low bedtime dose (10-25 mgr), which is gradually increased or titrated weekly, every 3-7 days (by 10-25 mgr/day), usually up to 150 mgr, or until further dose increase is forbidden due to adverse effects . Although TCAs analgesic properties probably occur at lower dosages than those for an antidepressant effect, no systematic evidence supporting this assumption exists. Some data suggest a possible dose-response relationship. An adequate trial of a TCA should have duration of 6-8 weeks, with at least 1 to 2 weeks at the maximum tolerated dosage. For NP, dosing escalation to antidepressant blood levels is advised for 4-6 weeks.

Common side-effects of TCAs are sedation, anticholinergic consequences (dry mouth, constipation, postural hypotension and weight gain) [94]. In one large-scale study, TCAs long term administration was associated with a 2.2-fold greater relative risk of myocardial infarction and a 1.7-fold increase in overall mortality, compared with placebo.

Other Antidepressants (ADs): SSRIs, SNRIs (Venlafaxine, Duloxetine), NDRIs (Bupropion)

Selective Serotonin Reuptake Inhibitors (SSRIs) produce less side-effects and are better tolerated than TCAs. At present, in NCP treatment there is insufficient evidence to support the use of SSRIs .

Sustained release bupropion, a Norepinephrine and Dopamine Reuptake Inhibitor (NDRI) was more effective than placebo in patients with NP of peripheral and central origin. It has a low incidence of sexual dysfunction and is associated with weight loss. Side-effects include agitation and insomnia. For NP it is given at a dosage of 150 – 300 mgr daily

Venlafaxine, with a different chemical structure compared to TCAs and SSRIs, inhibits norepinephrine and serotonin reuptake (SNRI) at a dose > 150 mgr daily. Recent data support the use of venlafaxine in NP states (NNT= 3.6). In a randomized, 3-period, crossover trial of venlafaxine and imipramine administered in patients with painful polyneuropathy, both antidepressants resulted in superior pain relief, compared with placebo, with no differences between them In a placebo-controlled, crossover trial of 13 patients with chronic NCP following breast cancer therapy (surgery, chemotherapy, radiotherapy) the investigators did not find significant benefits of venlafaxine (18.75-187.5 mgr/10weeks) vs placebo, regarding the primary end-point (daily pain dairy ratings), although venlafaxine was associated with better results related with two secondary pain end-points (maximum intensity of every day pain at rest and in movement). They also reported similar percentages of adverse effects vs placebo

Duloxetine, a newer dual uptake inhibitor, belongs to SNRIs, is FDA approved for PDN treatment, with early evidence of being efficacious. It has minimal or no effect on blood pressure and body weight, with few sexual adverse effects in studies published up to now. Duloxetine doses range between 60 and 120 mgr/day, without any significant differences between the two doses, but with better effect versus placebo. Improvement should be noted in 1 to 2 weeks at 60 mgr before increasing the dose, which should be considered prior to further dose elevation. Frequent adverse events observed were nausea, somnolence, dry mouth, constipation, diarrhoea, hyperhidrosis and dizziness, while discontinuation rates were 15-20% Duloxetine induces little or no cardiovascular side effects, but rare cases of hepatotoxicity have been published.

The advantage of venlafaxine and duloxetine application in NCP treatment is that, apart from pain relief, they can serve a useful therapeutic role for clinical depression

Antiepileptic Drugs (AEDs) – Gabapentinoids

Gabapentin is an AED, holding the broadest evidence for efficacy in NP treatment, due to central sensitization reduction. Loss of inhibitory regulation in the dorsal horn contributes to spontaneous firing of nociceptive pathways, through complex mechanisms. Levels of gamma-aminobutyric acid (GABA, a dorsal horn inhibitory transmitter) are reduced, and GABA receptors in dorsal horn neurons are down regulated. Gabapentin, an anticonvulsant structurally related to GABA and not acting on GABA receptors, is efficacious for the treatment of NP of various etiologies.

It has an FDA-approved indication for PHN in the United States and is licensed for the treatment of NP in the UK. Eight, at least, published double-blind, placebo-controlled, RCTs of gabapentin for chronic NP therapy exist in literature. These studies examined patients with PHN, PDN, mixed NP syndromes, phantom limb pain, Guillan-Barre syndrome and acute or chronic pain from spinal cord injury. Gabapentin at dosages up to 3600 mgr / day significantly reduced pain versus placebo; improvement in sleep, mood, and quality of life were also reported in some Confirmation from basic experimental studies, employing animal cancer pain models, as well as from clinical ones, concluded that gabapentin is effective in treating NCP. In a study investigating the efficacy and safety of gabapentin monotherapy in the management of CIPN, Gabapentin has also been studied in a multi-centre, randomized, double-blind, placebo-controlled trial, including 121 cancer patients with NCP. Patients had ineffective analgesia with opioids and they were started on gabapentin at a dose of 600-1800 mgr/day. The authors concluded that gabapentin is effective in improving analgesia in NCP patients, already treated with opioids. Side effects of gabapentin include somnolence, dizziness and less commonly gastrointestinal symptoms and mild peripheral oedema. All these effects require close monitoring and dosage adjustment, but usually not drug discontinuation.

Pregabalin has been FDA approved for PHN and PDN and its action is similar to that of gabapentin, with a significantly greater affinity for the a2-δ subunit of voltage-gated calcium channels versus gabapentin. Pain improvement is noted by the second day. It is not liver metabolized and as a result, important pharmacokinetic drug-drug interactions do not occur, but the dosage must be adjusted for patients with renal dysfunction. Its side effects are mild to moderate (dizziness, somnolence, headache, dry mouth and peripheral oedema). During the first 3 days 150 mgr daily are prescribed, followed by 300 mgr daily for the next 4 days. From the beginning of the second week 600 mgr/day are usually prescribed to patients, whose creatinine clearance is more than 60 ml/min (max dose 300 mgr twice a day) Pregabalin discontinuation rates range from 0 (150 mgr/day) to 20% (600 mgr/day).

As far as the therapeutic role of pregabalin in NCP management, in a study presented last year during the 3rd International Congress on Neuropathic Pain, we examined the results of the addition of pregabalin, in cancer patients with a NP component. In this prospective, open label study, we included 102 cancer patients with definite NCP, resistant to a combination of paracetamol, codeine, NSAIDs and methylprednisolone. Patients were randomly pided into two groups (pregabalin versus opioids). In the first group pregabalin was added and titrated up to 600 mgr/day, until significant pain relief or poor tolerability where observed (whichever occurred first). In the second group, TTS fentanyl 25mcg/h was added and the dose was escalated by 25 mcg/h every 72 hours, up to a maximum dose of 125 mcg/h, until significant pain relief or problematic tolerability. We concluded that pregabalin prescription in NCP patients provided significant pain alleviation and minimized the need for rescue opioids, thus reducing opioid-induced adverse effects and tolerance. However, in another recent publication on the treatment of CINP, the authors concluded that, unfortunately, even when effective in other types of NP, anticonvulsants and antiepileptics have not yet proven effective for treating CINP symptoms.

Topical Antineuralgics: 5% Lidocaine Patch, 5% Lidocaine Gel

Topical lidocaine is available as a 5% patch or gel. The efficacy of lidocaine patch has been demonstrated only in patients with PHN and focal NP syndromes, expressed with allodynia, without controlled studies being conducted for other pain conditions. Anecdotal evidence of a beneficial effect in patients who have other NP types has been published. In our department, we have used the 5% lidocaine patch in 36 patients in an open, observational study, for the treatment of NP of perse origin. The therapy had a 2-month to 4-year duration, resulting in good and very good analgesia in 50% of patients.

Lidocaine patches have been used in NCP where allodynia (sensitivity to light touch) exists . It has also been used for central NCP in a patient with metastatic epidural spinal cord compression, with promising results, offering new treatment options

Topical Antineuralgics: Capsaisin 8% Patch

A high concentration capsaicin patch (8%), applied to the skin for 60 min in 402 patients, was found to be more effective in treating NP versus a low concentration patch Adverse effects were primarily attributable to local capsaicin-related reactions at the application site. The patch has also been used for the treatment of painful HIV neuropathy In our department, we have used the Capsaisin 8% patch in patients with CIPN in an open, observational study with good unpublished yet results

NMDA Antagonists: Ketamine, Dextromethorphan, Amantadine,

The N-Methyl-D-Aspartate (NMDA) receptors within the spinal cord play a significant role in the pathophysiology of chronic NP. NMDA receptor antagonists have been used in an attempt to abolish wind-up at the spinal cord level. The role of excitatory amino acids in hyperalgesia and the development of tolerance to opioids were early recognized Ketamine and dextromethorphan are NMDA receptor antagonists, being explored for relieving NP. E. Ketamine is a potent analgesic at subanesthetic doses, by reducing hypersensitivity in the dorsal horn. Recently, it has been suggested that ketamine and amantadine reduce opioids resistant NCP

Conclusions

In conclusion, NCP is a complex pain problem that is often refractory to treatment. Its pathophysiology may involve perse aetiologies, which can vary with the evolution and progression of the disease. Present therapeutic strategies rely heavily upon pharmacotherapy. Combination of drugs, with completely different mechanisms of action is the optimal approach.

Recommended Reading

1) Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, Nurmikko T. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2009 revision. Eur J Neurol, 2010; 17: 1113 – 1123.

2) McGeeney BE. Adjuvant Agents in cancer pain. Clin J Pain, 2008; 24 (Suppl 10): S14 – S20.

3) Vadalouca A ,Siafaka I,Argyra E,Vrachnou E,Moka E. Therapeutic management of chronic Neuropathic Pain :an examination of pharmacologic treatment. Ann NY Acad Sci, 2006; 1088: 164 – 186.

4) Vadalouca, Raptis E, Moutzouri A, Stavropoulou E, Siafaka J, Argyra E. Pregabalin for the management of Neuropathic cancer pain.Preliminary results. Third International Congress on Neuropathic Pain of NeuPSIG. Athens, Greece, 2010; Abstract Book: page 73.

5) Emmanouil Anastassiou, Christos A. Iatrou, Nikolaos Vlaikidis, Marianthi Vafiadou, Georgia Stamatiou, Eleni Plesia, Leonidas Lyras and Athina Vadalouca, Impact of Pregabalin Treatment on Pain, Pain-Related Sleep Interference and General Well-Being in Patients with Neuropathic Pain. Clin Drug Investig, 2011; 31 (6): 417 – 426.

6) Vadalouca A et al. Pharmacological Treatment of Neuropathic Cancer Pain, Pain Practice, 2012; 12(3): 219 – 251.