**14. Pharmacological treatment of neuropathic pain**

Treating neuropathic pain requires a multifaceted approach that aims to eliminate the underlying etiology, when possible, and manage the associated discomforts and emotional distress. Although in some cases it is possible to directly treat the cause of neuropathic pain, for example surgery to alleviate a constricted nerve, it is more likely that the primary cause is untreatable, as is the case with singular traumatic events such as stroke and spinal cord injury and diseases like diabetes. When this is the case, symptom management and pain reduction become the primary focus. Unfortunately, in most cases complete elimination of pain is not a feasible endpoint; a pain reduction of 30% is considered to be efficacious [21]. Additionally, many pharmacological treatments require careful titration and tapering to prevent adverse effects and toxicity. This process may take several weeks to months, and ultimately the drug may be ineffective, necessitating another trial with a different medication. It is therefore necessary that both doctor and patient begin treatment with realistic expectations and goals.

First-line medications for the treatment of neuropathic pain are those that have proven efficacy in randomized clinical trials (RCTs) and are consistent with pooled clinical observations [81]. These include antidepressants, calcium channel ligands, and topical lidocaine [15]. Tricyclic antidepressants (TCAs) have demonstrated efficacy in treating neuropathic pain with positive results in RCTs for central post-stroke pain, PHN, painful diabetic and non-diabetic polyneur‐ opathy, and post-mastectomy pain syndrome [82]. However they do not seem to be effective in treating painful HIV-neuropathy or CIPN [82]. Duloxetine and venlafaxine, two selective serotonin norepinephrine reuptake inhibitors (SSNRIs), have been found to be effective in DPN and both DPN and painful polyneuropathies, respectively [81]. Adverse affects associated with TCAs and SSNRIs are relatively mild and can be mitigated by a slow titration beginning with

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Gabapentin and pregabalin have also demonstrated efficacy in several neuropathic pain conditions including DPN and PHN [81, 82]. Both drugs exert their effects by inhibiting neurotransmitter release through binding of the α2-δ subunit of presynaptic calcium channels [83]. Adverse effects and efficacy of gabapentin and pregabalin are similar; however prega‐ balin may provide more rapid analgesia due to straightforward dosing determined by linear pharmacokinetic [78]. Topical lidocaine (5% patch or gel) has significantly reduced allodynia associated with PHN and other neuropathic pain syndromes in several RCTs [81, 82]. With no reported systemic adverse effects and mild skin irritation as the only concern, lidocaine is an

In the event that first line medications, alone or in combination, are not effective at achieving adequate pain relief, second line medications may be considered. These include opioid analgesics and tramadol, pharmaceuticals which have proven efficacy in RCTs but are associated with significant adverse effects that warrant cautious prescription [15]. Although opioid analgesics are effective pain relievers in several types of neuropathic pain [81, 82, 84], they are associated with misuse or abuse, hypogonadism, constipation, nausea, and immu‐ nological changes [15]. Because many of these side effects can be mitigated by a low dose, careful titration, and short term use, opiates are an appropriate choice for treating acute or episodic neuropathic pain [81]. Careful consideration should be given when prescribing opiates to patients who have a personal or family history of drug or alcohol abuse, and

Tramadol, a weak opioid µ-receptor agonist and serotonin and norepinephrine reuptake inhibitor (SNRI), is more effective than placebo but less effective than strong opioid µ-receptor agonists (e.g. morphine and oxycodone) in treating neuropathic pain [82]. Although the risk is considerably less than opioid analgesics, tramadol is also associated with abuse [81]. A rare but potentially fatal serotonin syndrome has been described, and tramadol may increase the

Recent clinical trials have considered additional intervention strategies with possible utility in treatingneuropathicpain,althoughtheir efficacyremains tobedetermined.Treatments include botulinumtoxinforPHNandpostoperativeallodynia[85,86],highconcentrationcapsaisinpatch forthetreatmentofPHNandpainfulHIVneuropathy[15],andlacosamide,anantiepilepticdrug with suggested efficacy in treating DPN [87-89]. There is also accumulating evidence that

appropriate choice for treating localized peripheral neuropathic pain.

additional monitoring to ensure appropriate use may be necessary.

likelihood of seizures or interact with other medications [15].

a low dose [81].


**Table 1.** A list of bedside tests used to identify signs and symptoms that are suggestive of neuropathic pain.

Recently, the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Asso‐ ciation for the Study of Pain reviewed the evidence–based guidelines for the pharmacological treatment of neuropathic pain and made recommendations that take into account clinical efficacy, adverse effects, effects on health related quality of life, convenience, and cost [81]. These findings as well as more recent evidence are reviewed here.

First-line medications for the treatment of neuropathic pain are those that have proven efficacy in randomized clinical trials (RCTs) and are consistent with pooled clinical observations [81]. These include antidepressants, calcium channel ligands, and topical lidocaine [15]. Tricyclic antidepressants (TCAs) have demonstrated efficacy in treating neuropathic pain with positive results in RCTs for central post-stroke pain, PHN, painful diabetic and non-diabetic polyneur‐ opathy, and post-mastectomy pain syndrome [82]. However they do not seem to be effective in treating painful HIV-neuropathy or CIPN [82]. Duloxetine and venlafaxine, two selective serotonin norepinephrine reuptake inhibitors (SSNRIs), have been found to be effective in DPN and both DPN and painful polyneuropathies, respectively [81]. Adverse affects associated with TCAs and SSNRIs are relatively mild and can be mitigated by a slow titration beginning with a low dose [81].

for example surgery to alleviate a constricted nerve, it is more likely that the primary cause is untreatable, as is the case with singular traumatic events such as stroke and spinal cord injury and diseases like diabetes. When this is the case, symptom management and pain reduction become the primary focus. Unfortunately, in most cases complete elimination of pain is not a feasible endpoint; a pain reduction of 30% is considered to be efficacious [21]. Additionally, many pharmacological treatments require careful titration and tapering to prevent adverse effects and toxicity. This process may take several weeks to months, and ultimately the drug may be ineffective, necessitating another trial with a different medication. It is therefore necessary that both doctor and patient begin treatment with realistic expectations and goals.

14 Peripheral Neuropathy - A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder

**Signs and Symptoms Bedside Test Pathological Response**

Reduced sensation

Sharp burning superficial pain in putative lesion territory as well as

Sharp burning superficial pain in putative lesion territory as well as

as well as unaffected area

unaffected area

unaffected area

intervals for 30s Sharp pain with increasing intensity

Touch skin with cotton swab or

gauze

Paraesthesia Reported – grade intensity 1-10

Shooting Reported – grade intensity 1-10 Ongoing Reported – grade intensity 1-10

Dynamic Mechanical Move object (cotton swab or gauze)

Punctate Mechanical Pinprick with sharp object

Temporal Summation Pinprick with sharp object at 3s

These findings as well as more recent evidence are reviewed here.

along skin

Hypoalgesia Prick skin with pin Reduced sensation

Cold Touch skin object <20°C Painful, burning sensation Heat Touch skin object "/>40°C Painful, burning sensation

Static Mechanical Apply gentle pressure to skin Dull pain in putative lesion territory

Recently, the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Asso‐ ciation for the Study of Pain reviewed the evidence–based guidelines for the pharmacological treatment of neuropathic pain and made recommendations that take into account clinical efficacy, adverse effects, effects on health related quality of life, convenience, and cost [81].

**Table 1.** A list of bedside tests used to identify signs and symptoms that are suggestive of neuropathic pain.

*Abnormal Sensations*

Hypoesthesia

*Spontaneous Pain*

Allodynia/Hyperalgesia

*Evoked Pain*

Gabapentin and pregabalin have also demonstrated efficacy in several neuropathic pain conditions including DPN and PHN [81, 82]. Both drugs exert their effects by inhibiting neurotransmitter release through binding of the α2-δ subunit of presynaptic calcium channels [83]. Adverse effects and efficacy of gabapentin and pregabalin are similar; however prega‐ balin may provide more rapid analgesia due to straightforward dosing determined by linear pharmacokinetic [78]. Topical lidocaine (5% patch or gel) has significantly reduced allodynia associated with PHN and other neuropathic pain syndromes in several RCTs [81, 82]. With no reported systemic adverse effects and mild skin irritation as the only concern, lidocaine is an appropriate choice for treating localized peripheral neuropathic pain.

In the event that first line medications, alone or in combination, are not effective at achieving adequate pain relief, second line medications may be considered. These include opioid analgesics and tramadol, pharmaceuticals which have proven efficacy in RCTs but are associated with significant adverse effects that warrant cautious prescription [15]. Although opioid analgesics are effective pain relievers in several types of neuropathic pain [81, 82, 84], they are associated with misuse or abuse, hypogonadism, constipation, nausea, and immu‐ nological changes [15]. Because many of these side effects can be mitigated by a low dose, careful titration, and short term use, opiates are an appropriate choice for treating acute or episodic neuropathic pain [81]. Careful consideration should be given when prescribing opiates to patients who have a personal or family history of drug or alcohol abuse, and additional monitoring to ensure appropriate use may be necessary.

Tramadol, a weak opioid µ-receptor agonist and serotonin and norepinephrine reuptake inhibitor (SNRI), is more effective than placebo but less effective than strong opioid µ-receptor agonists (e.g. morphine and oxycodone) in treating neuropathic pain [82]. Although the risk is considerably less than opioid analgesics, tramadol is also associated with abuse [81]. A rare but potentially fatal serotonin syndrome has been described, and tramadol may increase the likelihood of seizures or interact with other medications [15].

Recent clinical trials have considered additional intervention strategies with possible utility in treatingneuropathicpain,althoughtheir efficacyremains tobedetermined.Treatments include botulinumtoxinforPHNandpostoperativeallodynia[85,86],highconcentrationcapsaisinpatch forthetreatmentofPHNandpainfulHIVneuropathy[15],andlacosamide,anantiepilepticdrug with suggested efficacy in treating DPN [87-89]. There is also accumulating evidence that intravenous Ca2+ and Mg2+ may be effective at preventing CIPN caused a commonly used chemotherapeutic, oxaliplatin, without attenuating its antineoplastic efficacy [9].

of patients who experience similar "symptom constellations" representing distinct pathophy‐ siological mechanisms [95]. Furthermore, these symptom constellations can be seen, albeit in different proportions, across neuropathic pain syndromes, suggesting that the same underly‐ ing mechanism can cause neuropathic pain within and apart from the initiating etiology. Hypothetically, with this understanding comes an approach of targeted treatment that aims to identify the pathophysiological mechanism and specifically inhibit, block, or enhance the offending molecules. To implement this type of treatment will require a more intimate understanding of the mechanisms of neuropathic pain and the corresponding symptom manifestations. As this becomes defined, specific treatments can begin to emerge, and clinical

**Signs and Symptoms Example Mechanisms Targeted Treatment**

Inflammation in nerve root, central sensitization (potentiation),

Modulation of TRPM8 or Na2+ channels in peripheral nociceptors

and facilitation), disinhibition

and facilitation), disinhibition

**Table 2.** Hypothetical examples of how signs and symptoms obtained in a bedside examination might indicate underlying pathophysiological mechanism. Once a putative mechanism has been established there is a potential for

Modulation of unknown mechanoreceptors in peripheral

nociceptors, TRPA1

selective and specifically targeted treatments to be applied. For a comprehensive review see [21].

Selective Na2+ channel blocker

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Cytokine antagonists, Calcium channel blocker, NMDA receptor

TRPM8 receptor antagonist, Selective Na2+ channel blocker

Ca2+ channel blocker, NMDA receptor antagonist

Ca2+ channel blocker, NMDA receptor antagonist

Ca2+ channel blocker, NMDA receptor antagonist

antagonist

nociceptors TRPV1 receptor antagonist

?

channel dysregulation

disinhibition

trials can test the efficacy of this approach. See Table 2 for examples.

Shooting Ectopic impulse generation, Na2+

Heat Modulation of TRPV1 in peripheral

Dynamic Mechanical Central sensitization (potentiation

Punctate Mechanical Central sensitization (potentiation

Temporal Summation Central sensitization

*Spontaneous Pain*

Ongoing

*Evoked Pain*

Cold

Allodynia/Hyperalgesia

Static Mechanical

### **15. Non-pharmacological treatment of neuropathic pain**

The use of alternative and complementary medicine is on the rise, particularly in the United States [90]. Although anecdotal evidence abounds, there are relatively few RCTs supporting the use of such therapies. It is important in considering these treatments, however, that the lack of evidence is not read as evidence of lacking efficacy. The scarcity of well controlled, robust clinical trials considering non-pharmacological treatments of chronic pain makes it difficult to recommend or dismiss these alternative treatments. A few studies have examined the use of acupuncture, herbal therapy, massage, hypnosis, and biofeedback on easing chronic pain but have yielded mixed results (for a review see [90]). The difficulty in standardizing treatment, inherent to these multi-faceted approaches, is a major obstacle in drawing reliable conclusions. Additionally, small sample sizes and lack of obvious controls are also significant barriers. Despite these hurdles, which obscure evidence-based conclusions, non-pharmaco‐ logical treatments are often prescribed in conjunction with evidence-based recommendations due to low risk of accompanying adverse effects.

Deep brain stimulation, a neurosurgical technique by which an implanted electrode delivers controlled electrical impulses to targeted brain regions, has demonstrated some efficacy in treating chronic pain but is not routinely employed due to a high risk-to-benefit ratio [91]. Targeting the periventricular/periaqueductal gray, internal capsule, and sensory thalamus has demonstrated efficacy in various pain conditions [91], but not all types of chronic pain are responsive. An intriguing new target, the NAc, has recently emerged as a potential site for deep brain stimulation as it has demonstrated efficacy in a case study of post-stroke pain [92]. As studies of pain processing in the brain have suggested, the pattern of activity in the NAc is divergent in nociceptive and chronic pain representation, validating this structure as a possible therapeutic target [69].

Another type of electro-stimulation device is emerging as a promising therapeutic tool for the treatment of neuropathic pain [93, 94]. Delivering repeated pulses of electrical stimulation trans-cutaneously, termed Scrambler therapy, has demonstrated some efficacy with lasting effects in CIPN [94], postsurgical pain, PHN, and spinal canal stenosis [93]. With few adverse effects and low associated risk, this may be a viable alternative to pharmacological treatment.
