**3. Recent pharmacotherapy for PHN**

To date, no clear predictors of treatment response have been identified in patients with neuropathic pain, including PHN. Various types of drugs have shown consistent efficacy in randomized clinical trials and meta-analysis [9]. The modes of action and information on dosing, precautions, and adverse events (AEs) for the different drug classes are summarized in Table 3 [9]. Numbers needed to treat (NNTs), numbers needed to harm (NNH) [26, 27] and AEs for the different drugs are shown in Table 4 [28].

Mode of action Major Adverse- events

Gabapentin Decreases release of

glutamate, noradrenaline, and substance P, with

ligands

channel

glutamate, noradrenaline, and substance P, with ligands on α2-δ subunit of voltagegated calcium channel

Blockage of sodium

µ-receptor agonism (oxycodone also

channels

causes к-receptor antagonism)

Pregabalin Decreases release of

5% lidocaine patch

Morphine, oxycodone, methadone, levorphanol on α2-δ subunit of voltage-gated calcium Precautions Other benefits

edema

interactions

sleep disturbance

Renal Insufficiency

Sedation, dizziness, Peripheral edema Renal Insufficiency

interactions,

Local erythema,

No systemic adverse events

History of substance abuse, suicide risk, driving impairment Rapid onset of analgesic effect

Rash None

Nausea/ vomiting, constipation, dizziness

No clinically significant drug

improvement of sleep disturbance and anxiety

Sedation, dizziness, peripheral

No clinically significant drug

Starting dose/maximum dose

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151

Duration of adequate trial

100-300 mg once to three times

daily/1200 mg three times daily; reduce if renal function impaired

50 mg three times daily or 75 mg twice daily/200 mg three times or 300 mg twice daily, reduce if renal function impaired Increase to 300 mg daily after 3-7 days, then by 150 mg daily every 3-7 days, as Tolerated 4 weeks

1-3 patches/3 patches

10-15 mg morphine every 4 h or as needed (equianalgesic doses

maximum doses After 1-2 weeks convert to long-acting

opioids/ transdermal application, use short-acting drug

should be used for other opioids)/no

None 2 weeks

Increase by 100-300 mg three times daily every 1-7 days as Tolerated 4 weeks

Titration

Predictive Factors for Postherpetic Neuralgia and Recent Pharmacotherapies

Among systemic therapies, tricyclic antidepressants (TCAs), calcium channel α2-δ ligands (gabapentin and pregabalin), and extended-release formulations of morphine and oxycodone show good efficacy in patients with PHN. Current guidelines suggest, perhaps to maximize the benefit-risk ratio, that TCAs should be preferred over opioids, and among TCAs, secondgeneration TCAs such as nortriptyline, desipramine, and imipramine are preferred over the first-generation agent, amitriptyline [29]. Opioids, specifically oxycodone, morphine, metha‐ done, and tramadol, are also effective against PHN. However, addiction and regulatory issues, coupled with the benign adverse event profile of anticonvulsants, make opioids a secondary choice in PHN [28].

The American Academy of Neurology (AAN; 2004), European Federation of Neurological Societies (NeuPSIG; 2007), and European Federation of Neurological Societies (EFNS; 2010) guidelines all recommend TCAs and pregabalin as first-line oral therapies for patients with PHN [11, 30, 31]. The NeuPSIG and EFNS guidelines also recommend gabapentin as first-line therapy for PHN. The NeuPSIG and EFNS guidelines state that secondary amine TCAs should generally be considered instead of the tertiary amine amitriptyline, due to the superior safety profiles [11, 29, 30].

Japan Society of Pain Clinicians (JSPC; 2011) guidelines recommend TCAs (particularly the secondary amines), calcium channel α2-δ ligands, and extract of cutaneous tissue of rabbits inoculated with vaccinia virus (Neurotropin®) as first-line oral therapies [32].



**3. Recent pharmacotherapy for PHN**

AEs for the different drugs are shown in Table 4 [28].

choice in PHN [28].

profiles [11, 29, 30].

Nortriptyline Desipramine

To date, no clear predictors of treatment response have been identified in patients with neuropathic pain, including PHN. Various types of drugs have shown consistent efficacy in randomized clinical trials and meta-analysis [9]. The modes of action and information on dosing, precautions, and adverse events (AEs) for the different drug classes are summarized in Table 3 [9]. Numbers needed to treat (NNTs), numbers needed to harm (NNH) [26, 27] and

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

Among systemic therapies, tricyclic antidepressants (TCAs), calcium channel α2-δ ligands (gabapentin and pregabalin), and extended-release formulations of morphine and oxycodone show good efficacy in patients with PHN. Current guidelines suggest, perhaps to maximize the benefit-risk ratio, that TCAs should be preferred over opioids, and among TCAs, secondgeneration TCAs such as nortriptyline, desipramine, and imipramine are preferred over the first-generation agent, amitriptyline [29]. Opioids, specifically oxycodone, morphine, metha‐ done, and tramadol, are also effective against PHN. However, addiction and regulatory issues, coupled with the benign adverse event profile of anticonvulsants, make opioids a secondary

The American Academy of Neurology (AAN; 2004), European Federation of Neurological Societies (NeuPSIG; 2007), and European Federation of Neurological Societies (EFNS; 2010) guidelines all recommend TCAs and pregabalin as first-line oral therapies for patients with PHN [11, 30, 31]. The NeuPSIG and EFNS guidelines also recommend gabapentin as first-line therapy for PHN. The NeuPSIG and EFNS guidelines state that secondary amine TCAs should generally be considered instead of the tertiary amine amitriptyline, due to the superior safety

Japan Society of Pain Clinicians (JSPC; 2011) guidelines recommend TCAs (particularly the secondary amines), calcium channel α2-δ ligands, and extract of cutaneous tissue of rabbits

Starting dose/maximum dose

25 mg at bedtime/150 mg daily Increase by 25 mg every 3-7 day as

Duration of adequate trial

6-8 weeks (at least 2 weeks Maximum tolerated dose)

Titration

tolerated

inoculated with vaccinia virus (Neurotropin®) as first-line oral therapies [32].

Precautions Other benefits

effects (e.g., dry mouth or urinary retention, weight gain) Cardiac disease , glaucoma, seizure disorder, use of tramadol Improvement of depression and

Sedation, ant-cholinergic

Mode of action Major Adverse- events

Inhibition of reuptake

serotonin and/or noradrenaline, blockage of sodium channels, anticholinergic

of


**3.1. Calcium hannel α2-δ Ligands**

*3.1.1. Pregabalin*

Gabapentin and pregabalin suppress the release of excitatory neurotransmitters on binding to the α2-δ subunit of potential-dependent calcium channels in the central nervous system (CNS). Both drugs are structurally similar and share similar mechanisms of action, but pregabalin shows a linear pharmacokinetic profile and strong affinity for the α2-δ subunit. Both drugs have been widely studied in peripheral pain syndromes, although pregabalin has been the focus of most studies in central neuropathic pain syndromes. Only a few drug interactions have been reported for both drugs and the agents are well tolerated, but must be used at lower doses in patients with decreased renal function [9, 32]. The EFNS, AAN, and NeuPSIG guidelines recommend the calcium channel α2-δ ligands gabapentin and/or pregabalin for the treatment of PHN [11, 29-31]. In a meta-analysis, NNTs before 1 patient achieves 50% pain reduction for gabapentin (3 trials, 559 patient episodes) and pregabalin (3 trials, 411 patient episodes) for a 50% reduction in pain were 4.4 and 4.9, respectively [27, 29] (Table 4). Subse‐ quent Cochrane reviews for both drugs calculated NNTs of 7.5 for gabapentin [29, 33] and 3.9 for pregabalin 600 mg [29, 34]. Gabapentin and pregabalin are effective and are the most

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153

commonly prescribed drugs in PHN because of their efficacy and benign AEs profile.

and does not alter GABA uptake or degradation [35].

Pregabalin is a 3-isobutyl derivative of gamma-amino butyric acid (GABA) with anti-convul‐ sant, anti-epileptic, anxiolytic, and analgesic activities. Although the exact mechanisms of action are unclear, pregabalin selectively binds to α2-δ subunits of presynaptic voltagedependent calcium channels located in the CNS. Binding of pregabalin to α2-δ subunits of presynaptic voltage-dependent calcium channels prevents calcium influx and the subsequent calcium-dependent release of various neurotransmitters, including glutamate, noradrenaline, serotonin (5-Hydroxytryptamine: 5-HT), dopamine, and substance P, from the presynaptic nerve terminals of hyperexcited neurons; synaptic transmission is inhibited and neuronal excitability is diminished. Pregabalin does not bind directly to GABA-A or GABA-B receptors

Pregabalin has also been associated with dose-related risks of somnolence (5-14%), dizziness (7-28%), and peripheral edema (6-16%) [29, 32, 34]. At a higher dose (600 mg/day), pregabalin has been associated with weight gain (9%), asthenia (9%), dry mouth (6%), and vertigo (5%) [28, 29, 36]. Discontinuations due to these AEs were ≤1% in patients treated with pregabalin at 150 mg/day and 4-15% in patients receiving a 600-mg/day dose. Serious AEs were reported in 2-5% of patients treated with pregabalin at 150, 300, and 600 mg/day, compared with 3% in those assigned to receive a placebo [29, 36]. Symptoms including insomnia, nausea, headache, and diarrhea were reported by some patients following abrupt withdrawal of pregabalin. Pregabalin should therefore be tapered gradually over a minimum of 1 week rather than discontinued abruptly. Weight gain noted in clinical trials of pregabalin was not limited to patients with peripheral edema. Weight gain was related to dose and duration of exposure to pregabalin, but did not appear to be associated with sex, age, or baseline body-mass index. A higher incidence of weight gain and peripheral edema were noted in patients taking both

Recommendations are all grading level A = good scientific evidence suggesting that the benefits of the treatment substantially outweigh the potential risks.


**Table 3.** Recommended first-line treatments for patients with PHN [9]

Values for NNTs and NNHs were adapted from Hempenstall et al. [27] and Wu and Raja [26]. NNTs for amitriptyline were based on studies by Watson et al. [49] and Max et al. [50].

\*The 95% confidence interval (CI) could not be determined by Hempenstall et al. [27] or by Wu and Raja [26].

ND, could not be determined by Hempenstall et al [27]; SSRIs, selective serotonin reuptake inhibitors; MAO, monoamine oxidase

**Table 4.** NNT, NNH, and adverse effects of selected drugs for PHN [28]

#### **3.1. Calcium hannel α2-δ Ligands**

Mode of action Major Adverse- events

**Table 3.** Recommended first-line treatments for patients with PHN [9]

Desipramine 1.9 (1.3-3.7) Minor harm: 4.8 (2.5-36.7)

Gabapentin 4.4 (3.3-6.1) Minor harm: 4.1 (3.2-5.7)

Pregabalin 4.9 (3.7-7.6) Minor harm: 4.3 (2.8-9.2)

Oxycodone 2.5 (1.7-4.4) Minor harm: 3.6 (2.2-10.2)

2.8 (2-4.6) ND

Tramadol 4.8 (3.5-6.0) Minor harm: 7.2\*

based on studies by Watson et al. [49] and Max et al. [50].

**Table 4.** NNT, NNH, and adverse effects of selected drugs for PHN [28]

4.2 (2.13-81.6)

Nortriptyline 3.7 (2.4-8) ND

substantially outweigh the potential risks.

Amitriptyline 1.6 (1.2-2.4)

Morphinecontrolled release or methadone

oxidase

Precautions Other benefits

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

Recommendations are all grading level A = good scientific evidence suggesting that the benefits of the treatment

**Drug NNT (95%CI) NNH (95%CI) Specific/Common Adverse Effects**

Minor harm: 8 (2.5-22) Major harm: 24 (8-36)

Major harm: 13\*

Major harm: ND

Major harm: 10.8\*

\*The 95% confidence interval (CI) could not be determined by Hempenstall et al. [27] or by Wu and Raja [26].

Values for NNTs and NNHs were adapted from Hempenstall et al. [27] and Wu and Raja [26]. NNTs for amitriptyline were

ND, could not be determined by Hempenstall et al [27]; SSRIs, selective serotonin reuptake inhibitors; MAO, monoamine

Major harm: 12.3 (7.7-30.2)

Major harm: 6.3 (4.2-12.8)

Starting dose/maximum dose

Sedation, dry mouth, tachycardia,

Somnolence, dry mouth, weight gain,

Immune suppression, loss of libido,

Somnolence, constipation, nausea and

seizures, serotonin syndrome when

with SSRIs and MAO inhibitors

Dizziness, somnolence, peripheral edema

prolonged QT interval

peripheral edema, ataxia

endocrine dysfunction

vomiting,

combined

constipation, urinary retention, weight gain,

Duration of adequate trial

as needed and as tolerated 4-6 weeks

Titration

Gabapentin and pregabalin suppress the release of excitatory neurotransmitters on binding to the α2-δ subunit of potential-dependent calcium channels in the central nervous system (CNS). Both drugs are structurally similar and share similar mechanisms of action, but pregabalin shows a linear pharmacokinetic profile and strong affinity for the α2-δ subunit. Both drugs have been widely studied in peripheral pain syndromes, although pregabalin has been the focus of most studies in central neuropathic pain syndromes. Only a few drug interactions have been reported for both drugs and the agents are well tolerated, but must be used at lower doses in patients with decreased renal function [9, 32]. The EFNS, AAN, and NeuPSIG guidelines recommend the calcium channel α2-δ ligands gabapentin and/or pregabalin for the treatment of PHN [11, 29-31]. In a meta-analysis, NNTs before 1 patient achieves 50% pain reduction for gabapentin (3 trials, 559 patient episodes) and pregabalin (3 trials, 411 patient episodes) for a 50% reduction in pain were 4.4 and 4.9, respectively [27, 29] (Table 4). Subse‐ quent Cochrane reviews for both drugs calculated NNTs of 7.5 for gabapentin [29, 33] and 3.9 for pregabalin 600 mg [29, 34]. Gabapentin and pregabalin are effective and are the most commonly prescribed drugs in PHN because of their efficacy and benign AEs profile.

#### *3.1.1. Pregabalin*

Pregabalin is a 3-isobutyl derivative of gamma-amino butyric acid (GABA) with anti-convul‐ sant, anti-epileptic, anxiolytic, and analgesic activities. Although the exact mechanisms of action are unclear, pregabalin selectively binds to α2-δ subunits of presynaptic voltagedependent calcium channels located in the CNS. Binding of pregabalin to α2-δ subunits of presynaptic voltage-dependent calcium channels prevents calcium influx and the subsequent calcium-dependent release of various neurotransmitters, including glutamate, noradrenaline, serotonin (5-Hydroxytryptamine: 5-HT), dopamine, and substance P, from the presynaptic nerve terminals of hyperexcited neurons; synaptic transmission is inhibited and neuronal excitability is diminished. Pregabalin does not bind directly to GABA-A or GABA-B receptors and does not alter GABA uptake or degradation [35].

Pregabalin has also been associated with dose-related risks of somnolence (5-14%), dizziness (7-28%), and peripheral edema (6-16%) [29, 32, 34]. At a higher dose (600 mg/day), pregabalin has been associated with weight gain (9%), asthenia (9%), dry mouth (6%), and vertigo (5%) [28, 29, 36]. Discontinuations due to these AEs were ≤1% in patients treated with pregabalin at 150 mg/day and 4-15% in patients receiving a 600-mg/day dose. Serious AEs were reported in 2-5% of patients treated with pregabalin at 150, 300, and 600 mg/day, compared with 3% in those assigned to receive a placebo [29, 36]. Symptoms including insomnia, nausea, headache, and diarrhea were reported by some patients following abrupt withdrawal of pregabalin. Pregabalin should therefore be tapered gradually over a minimum of 1 week rather than discontinued abruptly. Weight gain noted in clinical trials of pregabalin was not limited to patients with peripheral edema. Weight gain was related to dose and duration of exposure to pregabalin, but did not appear to be associated with sex, age, or baseline body-mass index. A higher incidence of weight gain and peripheral edema were noted in patients taking both pregabalin and a thiazolidinedione, compared with patients taking either agent alone. As a result, care should be taken when co-administering pregabalin and one of these agents [37].

In the JSPC guideline, although multiple clinical studies have demonstrated the analgesic effects of opioid analgesics (narcotics for medical use) in patients with neuropathic pain, opioids are generally recommended as second- or third-line treatment for several reasons. First, opioid analgesics have a high incidence of associated AEs that may persist over the entire course of treatment. Second, the lack of any systematic investigation into the long-term safety of opioid analgesics means that the opioid analgesics may not be fundamentally safer than other drug options. Third, opioid analgesics may cause hyperalgesia. This effect, if present, would adversely modify the risk/benefit profile of long-term treatment in neuropathic pain

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The sulfate salt of morphine is an opiate alkaloid isolated from the plant Papaver somniferum and produced synthetically. Morphine binds to and activates specific opiate receptors (δ, µ and κ), each of which are involved in controlling different brain functions. In the CNS and gastroin‐ testinal system, this agent exerts widespread effects including analgesia, anxiolysis, euphoria, sedation,respiratorydepression, andsmoothmuscle contractioninthe gastrointestinal system.

A sustained-release tablet formulation contains the sulfate salt of the opiate alkaloid morphine to provide analgesic activity. Morphine binds to and activates µ-opioid receptors in the CNS, thereby mimicking the effects of endogenous opioids. Binding of morphine to opioid receptors stimulates exchange of guanosine 5'-triphosphate for guanosine 5'-diphosphate, inhibits adenylate cyclase, and decreases intracellular cyclic adenosine monophosphate. This inhibits the release of various nociceptive neurotransmitters, such as substance P, GABA, dopamine, acetylcholine, noradrenaline, vasopressin, and somatostatin. In addition, morphine closes Ntype voltage-gated calcium channels and opens calcium-dependent inwardly rectifying potassium channels, causing hyperpolarization of neuronal membranes and reductions in

The hydrochloride salt of oxycodone is a methylether of oxymorphone and a semisynthetic opioid agonist with analgesic and antitussive properties. Oxycodone binds to µ-receptors in the CNS, thereby mimicking the effects of endogenous opiates as well as morphine. In addition to analgesia and a depressive effect on the cough center in the medulla, this agent may cause euphoria, anxiolysis, miosis, sedation, physical dependence, constipation, and respiratory

A synthetic codeine analogue, tramadol has central analgesic properties with effects similar to opioids, such as morphine and codeine, acting on specific opioid receptors. Used as a narcotic analgesic for severe pain, this agent can be addictive. Tramadol is used to treat moderate-toseverepaininadults,andbindstoopioidreceptorsintheCNS[41].Tramadolalsoweaklyinhibits noradrenaline and 5-HT reuptake and can therefore interact with serotonergic drugs (selec‐

depression, depending on dosage and variations in individual metabolism [35].

patients. Finally, opioid abuse and addiction are substantial problems [32].

neuronal excitability, with subsequent analgesia and sedation [35].

*3.2.1. Morphine*

*3.2.2. Oxycodone hydrochloride*

*3.2.3. Tramadol*

JSPC guidelines recommend beginning pregabalin treatment at 75 mg/day once before bed, 150 mg/day as two doses after breakfast and supper, or 150 mg/day as three doses after each meal. Even when renal function is normal, consider a very low dose only just before bed, such as 25 mg/day once before bed, for elderly patients, patients of low body weight, and others prone to AEs [32].

#### *3.1.2. Gabapentin*

Gabapentin is a synthetic analogue of the neurotransmitter GABA with anticonvulsant activity. Although the exact mechanisms of action are unknown, gabapentin appears to inhibit excitatory neuron activity. This agent also exhibits analgesic properties [35].

In clinical trials, the most frequent AEs observed with gabapentin were somnolence (16%), dizziness (21%), and peripheral edema (8%) [33]. Twelve percent of patients discontinued gabapentin owing to AEs, compared with 8% who discontinued placebo. Serious AEs with gabapentin and placebo occurred in 4% and 3% of patients, respectively [29].

#### **3.2. Opioids**

Opioid analgesics are agonists at presynaptic and postsynaptic opioid receptors. Opioids offer comparable analgesic efficacy to TCAs. Concerns about long-term AEs, such as immunological changes, physical dependency, and misuse or abuse, can limit the use of strong opioids in patients with neuropathic non-cancer-related pain [9].

The place of opioids and tramadol in guidelines for the management of PHN has evolved over time. In the 2004 AAN guidelines, extended-release formulations of oxycodone and morphine were recommended as first-line agents. Guidelines issued by the NeuPSIG (2007) and EFNS (2010) recommend strong opioids and tramadol as second-line therapy, not because of new data on efficacy, but perhaps reflecting concerns about the risks of AEs and abuse [29].

Extended-release formulations of oxycodone [38] and morphine, as well as methadone [39], have shown efficacy in patients with PHN. The NNT for a 50% reduction in pain were 2.5 for oxycodone and 2.8 for morphine or methadone, compared with an NNT of 3.7 for the TCA nortriptyline (Table 4). In a placebo-controlled, active comparator-controlled crossover trial, the majority of patients (53%) preferred the opioids morphine or methadone over TCAs. Opioids tended to provide greater pain relief, although the difference was not significant [40]. A meta-analysis of the 2 trials evaluating oxycodone, morphine and methadone calculated an NNT for opioids of 2.7 [27]. Tramadol has proven less effective than strong opioids. In a randomized controlled trial, tramadol was not significantly better than placebo on a 5-point verbal scale or on measures of quality of life [40]. An analysis of this trial calculated an NNT of 4.8 [27]. Oxycodone, morphine, and methadone were associated with typical opioid-related AEs, including nausea, diarrhea, and constipation [38, 39]. Tramadol was better tolerated, but less effective [40].

In the JSPC guideline, although multiple clinical studies have demonstrated the analgesic effects of opioid analgesics (narcotics for medical use) in patients with neuropathic pain, opioids are generally recommended as second- or third-line treatment for several reasons. First, opioid analgesics have a high incidence of associated AEs that may persist over the entire course of treatment. Second, the lack of any systematic investigation into the long-term safety of opioid analgesics means that the opioid analgesics may not be fundamentally safer than other drug options. Third, opioid analgesics may cause hyperalgesia. This effect, if present, would adversely modify the risk/benefit profile of long-term treatment in neuropathic pain patients. Finally, opioid abuse and addiction are substantial problems [32].

#### *3.2.1. Morphine*

pregabalin and a thiazolidinedione, compared with patients taking either agent alone. As a result, care should be taken when co-administering pregabalin and one of these agents [37].

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

JSPC guidelines recommend beginning pregabalin treatment at 75 mg/day once before bed, 150 mg/day as two doses after breakfast and supper, or 150 mg/day as three doses after each meal. Even when renal function is normal, consider a very low dose only just before bed, such as 25 mg/day once before bed, for elderly patients, patients of low body weight, and others

Gabapentin is a synthetic analogue of the neurotransmitter GABA with anticonvulsant activity. Although the exact mechanisms of action are unknown, gabapentin appears to inhibit

In clinical trials, the most frequent AEs observed with gabapentin were somnolence (16%), dizziness (21%), and peripheral edema (8%) [33]. Twelve percent of patients discontinued gabapentin owing to AEs, compared with 8% who discontinued placebo. Serious AEs with

Opioid analgesics are agonists at presynaptic and postsynaptic opioid receptors. Opioids offer comparable analgesic efficacy to TCAs. Concerns about long-term AEs, such as immunological changes, physical dependency, and misuse or abuse, can limit the use of strong opioids in

The place of opioids and tramadol in guidelines for the management of PHN has evolved over time. In the 2004 AAN guidelines, extended-release formulations of oxycodone and morphine were recommended as first-line agents. Guidelines issued by the NeuPSIG (2007) and EFNS (2010) recommend strong opioids and tramadol as second-line therapy, not because of new data on efficacy, but perhaps reflecting concerns about the risks of AEs and abuse [29].

Extended-release formulations of oxycodone [38] and morphine, as well as methadone [39], have shown efficacy in patients with PHN. The NNT for a 50% reduction in pain were 2.5 for oxycodone and 2.8 for morphine or methadone, compared with an NNT of 3.7 for the TCA nortriptyline (Table 4). In a placebo-controlled, active comparator-controlled crossover trial, the majority of patients (53%) preferred the opioids morphine or methadone over TCAs. Opioids tended to provide greater pain relief, although the difference was not significant [40]. A meta-analysis of the 2 trials evaluating oxycodone, morphine and methadone calculated an NNT for opioids of 2.7 [27]. Tramadol has proven less effective than strong opioids. In a randomized controlled trial, tramadol was not significantly better than placebo on a 5-point verbal scale or on measures of quality of life [40]. An analysis of this trial calculated an NNT of 4.8 [27]. Oxycodone, morphine, and methadone were associated with typical opioid-related AEs, including nausea, diarrhea, and constipation [38, 39]. Tramadol was better tolerated, but

excitatory neuron activity. This agent also exhibits analgesic properties [35].

gabapentin and placebo occurred in 4% and 3% of patients, respectively [29].

patients with neuropathic non-cancer-related pain [9].

prone to AEs [32].

*3.1.2. Gabapentin*

**3.2. Opioids**

less effective [40].

The sulfate salt of morphine is an opiate alkaloid isolated from the plant Papaver somniferum and produced synthetically. Morphine binds to and activates specific opiate receptors (δ, µ and κ), each of which are involved in controlling different brain functions. In the CNS and gastroin‐ testinal system, this agent exerts widespread effects including analgesia, anxiolysis, euphoria, sedation,respiratorydepression, andsmoothmuscle contractioninthe gastrointestinal system.

A sustained-release tablet formulation contains the sulfate salt of the opiate alkaloid morphine to provide analgesic activity. Morphine binds to and activates µ-opioid receptors in the CNS, thereby mimicking the effects of endogenous opioids. Binding of morphine to opioid receptors stimulates exchange of guanosine 5'-triphosphate for guanosine 5'-diphosphate, inhibits adenylate cyclase, and decreases intracellular cyclic adenosine monophosphate. This inhibits the release of various nociceptive neurotransmitters, such as substance P, GABA, dopamine, acetylcholine, noradrenaline, vasopressin, and somatostatin. In addition, morphine closes Ntype voltage-gated calcium channels and opens calcium-dependent inwardly rectifying potassium channels, causing hyperpolarization of neuronal membranes and reductions in neuronal excitability, with subsequent analgesia and sedation [35].

#### *3.2.2. Oxycodone hydrochloride*

The hydrochloride salt of oxycodone is a methylether of oxymorphone and a semisynthetic opioid agonist with analgesic and antitussive properties. Oxycodone binds to µ-receptors in the CNS, thereby mimicking the effects of endogenous opiates as well as morphine. In addition to analgesia and a depressive effect on the cough center in the medulla, this agent may cause euphoria, anxiolysis, miosis, sedation, physical dependence, constipation, and respiratory depression, depending on dosage and variations in individual metabolism [35].

#### *3.2.3. Tramadol*

A synthetic codeine analogue, tramadol has central analgesic properties with effects similar to opioids, such as morphine and codeine, acting on specific opioid receptors. Used as a narcotic analgesic for severe pain, this agent can be addictive. Tramadol is used to treat moderate-toseverepaininadults,andbindstoopioidreceptorsintheCNS[41].Tramadolalsoweaklyinhibits noradrenaline and 5-HT reuptake and can therefore interact with serotonergic drugs (selec‐ tive noradrenaline reuptake inhibitors [SNRIs] and selective serotonin reuptake inhibitors [SSRIs]), causing serotonin syndrome, although this risk seems to be low in clinical practice [9].

TCAs, the selective 5-HT and noradrenaline reuptake inhibitors (SSNRIs) offer efficacy for both pain and depression with fewer AEs. SSRIs effectively relieve depression symptoms but they do not specifically relieve neuropathic pain. Nevertheless, some patients with chronic pain due to PHN will experience clinical depression, and the use of SSRIs can be useful for the

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SNRIs are safer and easier to use than TCAs and represent a better option for patients with heart disease. The mechanism of SNRI analgesia is likely associated with activation of the

The hydrochloride salt form of paroxetine is a phenylpiperidine derivative and a SSRI with antidepressant and anxiolytic properties. Paroxetine binds to the pre-synaptic serotonin transporter complex, resulting in negative allosteric modulation of the complex and thereby blocking reuptake of serotonin by the pre-synaptic transporter. Inhibition of serotonin recycling enhances serotonergic function through serotonin accumulation in the synaptic cleft, resulting in long-term desensitization and downregulation of 5-HT receptors and leading to

The hydrochloride salt of duloxetine is a fluoxetine derivative belonging to the class of SSNRIs and exhibiting antidepressant activity. Duloxetine selectively prevents reuptake of 5-HT and noradrenaline via transporter complexes on the pre-synaptic membrane, thereby increasing the levels of these neurotransmitters within the synaptic cleft. As a result, this agent potentiates serotonergic and noradrenergic activities in the CNS, alleviating depression and neuropathic sensations such as pain and tingling. Furthermore, duloxetine does not show significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamatergic, or

Duloxetine is recommended for painful diabetic neuropathies [11, 29, 30], but not for PHN; little clinical trial data has been accumulated supporting use in PHN. SNRIs are also associated with a number of systemic AEs, including nausea, vomiting, somnolence, anorexia, constipa‐

Several other oral agents have been investigated in the treatment of PHN. Specifically, the NMDA antagonists dextromethorphan and memantine [55, 56] and the benzodiazepine

In treatment guidelines, therapies described as lacking sufficient evidence of efficacy include anticonvulsants that target sodium channels (carbamazepine and oxcarbazepine), other anticonvulsants (lamotrigine, topiramate, and valproic acid), other antidepressants (bupro‐ pion, citalopram, paroxetine), and the oral lidocaine analog, mexiletine [11, 30, 31]. For other

tion, dizziness, fatigue, insomnia, increased sweating, and dry mouth [52-54].

lorazepam [56] have not shown good efficacy in clinical trials.

management of depressive symptoms [5].

descending inhibitory system of pain.

symptomatic relief of depressive illness [35].

*3.4.1. Paroxetine hydrochloride*

*3.4.2. Duloxetine hydrochloride*

GABAergic receptors [35].

**3.5. Other oral therapies**

#### **3.3. TCAs**

Clinical data support the efficacy of TCAs for PHN. In a 2005 meta-analysis of 4 clinical trials (248 patient episodes), the NNT for 1 patient to achieve a 50% reduction in pain with the TCAs amitriptyline, nortriptyline, and desipramine was 2.6 [27]. A 2007 Cochrane review of 4 clinical trials (244 patients) calculated an NNT of 2.7 [41]. Although effective, TCAs have been associated with significant systemic AEs, most notably anticholinergic AEs [43, 44], and have been associated with cardiotoxicity [45-47]. Electrocardiography (ECG) before the start of treatment is mandatory and careful dose titration is needed [9]. Individual trials of amitripty‐ line and desipramine in patients with PHN suggest that the second-generation TCA desipra‐ mine produces fewer anticholinergic side effects than amitriptyline [48, 49].

#### *3.3.1. Amitriptyline hydrochloride*

The hydrochloride salt of the tricyclic dibenzocycloheptadiene amitriptyline with antidepres‐ sant and antinociceptive activities. Amitriptyline hydrochloride is the hydrochloride salt of the tricyclic dibenzocycloheptadiene amitriptyline, and shows antidepressant and antinoci‐ ceptive activities. Amitriptyline inhibits the re-uptake of noradrenaline and serotonin by the presynaptic neuronal membrane in the CNS, thereby increasing synaptic concentrations of noradrenaline and serotonin. Due to constant stimulation of these receptors, amitriptyline may produce a downregulation of adrenergic and serotonin receptors, which may contribute to the antidepressant activity. In the CNS, the antinociceptive activity of this agent may involve highaffinity binding to and inhibition of N-methyl-D-aspartate (NMDA) receptors and/or en‐ hancement of the action of serotonin at the spinal terminals of an opioid-mediated intrinsic analgesia system [35].

Amitriptyline has an NNT of 2.2 for PHN, but the AEs, lack of recommendations for use in the elderly, and small sample sizes of studies have relegated this agent behind antiepileptics for certain PHN cases [30, 42, 50, 51]. Nortriptyline, maprotiline, and desipramine have also proven effective, but less so than amitriptyline.

#### *3.3.2. Nortriptyline*

A TCA used for short-term treatment of various forms of depression, nortriptyline blocks the noradrenaline presynaptic receptors, thereby blocking reuptake of this neurotransmitter and raising concentrations in the synaptic cleft in the CNS. Nortriptyline also binds to α-adrenergic, histaminergic and cholinergic receptors. Long-term treatment with nortriptyline produces downregulation of adrenergic receptors due to increased stimulation of these receptors [41].

#### **3.4. Selective serotonin and noradrenaline reuptake inhibitors**

Patients who are unable to tolerate TCAs may do better with selective serotonin and noradre‐ naline reuptake inhibitors, such as duloxetine or venlafaxine. Although less effective than TCAs, the selective 5-HT and noradrenaline reuptake inhibitors (SSNRIs) offer efficacy for both pain and depression with fewer AEs. SSRIs effectively relieve depression symptoms but they do not specifically relieve neuropathic pain. Nevertheless, some patients with chronic pain due to PHN will experience clinical depression, and the use of SSRIs can be useful for the management of depressive symptoms [5].

SNRIs are safer and easier to use than TCAs and represent a better option for patients with heart disease. The mechanism of SNRI analgesia is likely associated with activation of the descending inhibitory system of pain.

#### *3.4.1. Paroxetine hydrochloride*

tive noradrenaline reuptake inhibitors [SNRIs] and selective serotonin reuptake inhibitors [SSRIs]), causing serotonin syndrome, although this risk seems to be low in clinical practice [9].

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

Clinical data support the efficacy of TCAs for PHN. In a 2005 meta-analysis of 4 clinical trials (248 patient episodes), the NNT for 1 patient to achieve a 50% reduction in pain with the TCAs amitriptyline, nortriptyline, and desipramine was 2.6 [27]. A 2007 Cochrane review of 4 clinical trials (244 patients) calculated an NNT of 2.7 [41]. Although effective, TCAs have been associated with significant systemic AEs, most notably anticholinergic AEs [43, 44], and have been associated with cardiotoxicity [45-47]. Electrocardiography (ECG) before the start of treatment is mandatory and careful dose titration is needed [9]. Individual trials of amitripty‐ line and desipramine in patients with PHN suggest that the second-generation TCA desipra‐

The hydrochloride salt of the tricyclic dibenzocycloheptadiene amitriptyline with antidepres‐ sant and antinociceptive activities. Amitriptyline hydrochloride is the hydrochloride salt of the tricyclic dibenzocycloheptadiene amitriptyline, and shows antidepressant and antinoci‐ ceptive activities. Amitriptyline inhibits the re-uptake of noradrenaline and serotonin by the presynaptic neuronal membrane in the CNS, thereby increasing synaptic concentrations of noradrenaline and serotonin. Due to constant stimulation of these receptors, amitriptyline may produce a downregulation of adrenergic and serotonin receptors, which may contribute to the antidepressant activity. In the CNS, the antinociceptive activity of this agent may involve highaffinity binding to and inhibition of N-methyl-D-aspartate (NMDA) receptors and/or en‐ hancement of the action of serotonin at the spinal terminals of an opioid-mediated intrinsic

Amitriptyline has an NNT of 2.2 for PHN, but the AEs, lack of recommendations for use in the elderly, and small sample sizes of studies have relegated this agent behind antiepileptics for certain PHN cases [30, 42, 50, 51]. Nortriptyline, maprotiline, and desipramine have also

A TCA used for short-term treatment of various forms of depression, nortriptyline blocks the noradrenaline presynaptic receptors, thereby blocking reuptake of this neurotransmitter and raising concentrations in the synaptic cleft in the CNS. Nortriptyline also binds to α-adrenergic, histaminergic and cholinergic receptors. Long-term treatment with nortriptyline produces downregulation of adrenergic receptors due to increased stimulation of these receptors [41].

Patients who are unable to tolerate TCAs may do better with selective serotonin and noradre‐ naline reuptake inhibitors, such as duloxetine or venlafaxine. Although less effective than

mine produces fewer anticholinergic side effects than amitriptyline [48, 49].

**3.3. TCAs**

*3.3.1. Amitriptyline hydrochloride*

analgesia system [35].

*3.3.2. Nortriptyline*

proven effective, but less so than amitriptyline.

**3.4. Selective serotonin and noradrenaline reuptake inhibitors**

The hydrochloride salt form of paroxetine is a phenylpiperidine derivative and a SSRI with antidepressant and anxiolytic properties. Paroxetine binds to the pre-synaptic serotonin transporter complex, resulting in negative allosteric modulation of the complex and thereby blocking reuptake of serotonin by the pre-synaptic transporter. Inhibition of serotonin recycling enhances serotonergic function through serotonin accumulation in the synaptic cleft, resulting in long-term desensitization and downregulation of 5-HT receptors and leading to symptomatic relief of depressive illness [35].

#### *3.4.2. Duloxetine hydrochloride*

The hydrochloride salt of duloxetine is a fluoxetine derivative belonging to the class of SSNRIs and exhibiting antidepressant activity. Duloxetine selectively prevents reuptake of 5-HT and noradrenaline via transporter complexes on the pre-synaptic membrane, thereby increasing the levels of these neurotransmitters within the synaptic cleft. As a result, this agent potentiates serotonergic and noradrenergic activities in the CNS, alleviating depression and neuropathic sensations such as pain and tingling. Furthermore, duloxetine does not show significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamatergic, or GABAergic receptors [35].

Duloxetine is recommended for painful diabetic neuropathies [11, 29, 30], but not for PHN; little clinical trial data has been accumulated supporting use in PHN. SNRIs are also associated with a number of systemic AEs, including nausea, vomiting, somnolence, anorexia, constipa‐ tion, dizziness, fatigue, insomnia, increased sweating, and dry mouth [52-54].

#### **3.5. Other oral therapies**

Several other oral agents have been investigated in the treatment of PHN. Specifically, the NMDA antagonists dextromethorphan and memantine [55, 56] and the benzodiazepine lorazepam [56] have not shown good efficacy in clinical trials.

In treatment guidelines, therapies described as lacking sufficient evidence of efficacy include anticonvulsants that target sodium channels (carbamazepine and oxcarbazepine), other anticonvulsants (lamotrigine, topiramate, and valproic acid), other antidepressants (bupro‐ pion, citalopram, paroxetine), and the oral lidocaine analog, mexiletine [11, 30, 31]. For other

neuropathic pain syndromes, mexiletine has only shown efficacy at doses that produce systemic AEs, including proarrhythmic effects [43]. This suggests that the benefits of sodium channel antagonism for PHN may be better achieved via local lidocaine administration.

a relevant systemic absorption offers a good benefit-to-risk ratio only with local AEs, such as

Predictive Factors for Postherpetic Neuralgia and Recent Pharmacotherapies

http://dx.doi.org/10.5772/55278

159

The transdermal patch contains a 5% aqueous base solution of the synthetic amide-type anesthetic lidocaine with analgesic activity. Upon topical application and transdermal delivery, the active ingredient lidocaine binds to and blocks voltage-gated sodium channels in the neuronal cell membrane; lidocaine-mediated stabilization of neuronal membranes inhibits the initiation and conduction of nerve impulses and produces reversible local anes‐ thesia [34]. The lidocaine 5% patch is recommended as first-line therapy in the AAN [31],

In clinical practice, a combination of two or more drugs is often needed to achieve satisfactory pain relief, although few trials have been conducted to support this clinical observation. However, combination therapy with gabapentin or pregabalin and extended-release morphine in patients with PHN achieved higher pain relief with lower doses compared to administration of one drug alone. These results have also been confirmed for the combination of nortriptyline and gabapentin as well as for pregabalin and topical lidocaine in patients with PHN. Taken together, these results substantiate the usefulness of combination therapies in patients with

Neither obvious pathogenesis nor an established treatment have been clarified or established for PHN. Our study indicated that advanced age and deep pain at the first visit were shown to be predictive factors for PHN. DM and pain reduced by bathing should also be considered as potential predictors of PHN. We further reviewed recent pharmacotherapeutic results for PHN. To improve patient safety and the likelihood of achieving satisfactory outcomes, prospective studies are needed to establish optimal treatments including pharmacotherapy

1 Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Graduate

2 Pain Treatment & Palliative Care Unit, University Hospital, Kyoto Prefectural University

erythema or rash [9].

**3.6. Combination therapy**

PHN [9].

for PHN.

**Author details**

Yuko Kanbayashi1,2\* and Toyoshi Hosokawa2,3,4

School of Medical Science, Kyoto, Japan

\*Address all correspondence to: ykokanba@koto.kpu-m.ac.jp

of Medicine, Graduate School of Medical Science, Kyoto, Japan

**4. Conclusion**

NeuPSIG [30], and EFNS [11] guidelines [29].

JSPC guidelines also recommend extract of cutaneous tissue from rabbits inoculated with vaccinia virus (Neurotropin®) as a first-line oral therapy[32].

#### *3.5.1. Carbamazepine*

Carbamazepine is a tricyclic compound chemically related to TCAs with anticonvulsant and analgesic properties. This agent exerts anticonvulsant activity by reducing polysynaptic responses and blocking post-tetanic potentiation. The analgesic activity is not understood, but carbamazepine is commonly used to treat pain associated with trigeminal neuralgia [35].

#### *3.5.2. Valproic acid*

Valproic acid is a synthetic derivative of propylpentanoic acid with antiepileptic properties and potential antineoplastic and antiangiogenesis activities. In epilepsy, valproic acid appears to act by increasing concentrations of GABA in the brain. The antitumor and antiangiogenesis activities of this agent may be related to the inhibition of histone deacetylases and nitric oxide synthase, resulting in the inhibition of nitric oxide synthesis [35].

#### *3.5.3. Extract of cutaneous tissue from rabbits inoculated with vaccinia virus*

Extract of cutaneous tissue from rabbits inoculated with vaccinia virus (Neurotropin®) has been shown to exert analgesic effects in a Japanese clinical study in PHN as one type of neuropathic pain. Producing no serious AEs, the drug product was very well tolerated, in addition to conferring analgesic effects. The drug product has been clinically used in patients 20 years old and older and is very safe [32, 57, 58].

#### *3.5.4. Antiarrhythmics (mexiletine)*

Mexiletine hydrochloride is a class 1B antiarrhythmic, and works by blocking sodium channels. A local anesthetic and antiarrhythmic (Class IB) agent structurally related to lidocaine, mexiletine exerts antiarrhythmic effects by inhibiting the inward sodium current in cardiac cells, thus reducing the rate of increase in the cardiac action potential (phase 0) and decreasing automaticity in Purkinje fibers. This slows nerve impulses in the heart and stabilizes the heartbeat. The anesthetic activity is due to the ability of mexiletine to block sodium influx in peripheral nerves, thereby reducing the rate and intensity of pain impulses reaching the CNS [41].

#### *3.5.5. Lidocaine patch 5%*

Lidocaine relieves pain through non-specific blockage of sodium channels on ectopic periph‐ eral afferent fibers without causing numbness of the treated skin. Topical application without a relevant systemic absorption offers a good benefit-to-risk ratio only with local AEs, such as erythema or rash [9].

The transdermal patch contains a 5% aqueous base solution of the synthetic amide-type anesthetic lidocaine with analgesic activity. Upon topical application and transdermal delivery, the active ingredient lidocaine binds to and blocks voltage-gated sodium channels in the neuronal cell membrane; lidocaine-mediated stabilization of neuronal membranes inhibits the initiation and conduction of nerve impulses and produces reversible local anes‐ thesia [34]. The lidocaine 5% patch is recommended as first-line therapy in the AAN [31], NeuPSIG [30], and EFNS [11] guidelines [29].

### **3.6. Combination therapy**

neuropathic pain syndromes, mexiletine has only shown efficacy at doses that produce systemic AEs, including proarrhythmic effects [43]. This suggests that the benefits of sodium channel antagonism for PHN may be better achieved via local lidocaine administration.

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

JSPC guidelines also recommend extract of cutaneous tissue from rabbits inoculated with

Carbamazepine is a tricyclic compound chemically related to TCAs with anticonvulsant and analgesic properties. This agent exerts anticonvulsant activity by reducing polysynaptic responses and blocking post-tetanic potentiation. The analgesic activity is not understood, but carbamazepine is commonly used to treat pain associated with trigeminal neuralgia [35].

Valproic acid is a synthetic derivative of propylpentanoic acid with antiepileptic properties and potential antineoplastic and antiangiogenesis activities. In epilepsy, valproic acid appears to act by increasing concentrations of GABA in the brain. The antitumor and antiangiogenesis activities of this agent may be related to the inhibition of histone deacetylases and nitric oxide

Extract of cutaneous tissue from rabbits inoculated with vaccinia virus (Neurotropin®) has been shown to exert analgesic effects in a Japanese clinical study in PHN as one type of neuropathic pain. Producing no serious AEs, the drug product was very well tolerated, in addition to conferring analgesic effects. The drug product has been clinically used in patients

Mexiletine hydrochloride is a class 1B antiarrhythmic, and works by blocking sodium channels. A local anesthetic and antiarrhythmic (Class IB) agent structurally related to lidocaine, mexiletine exerts antiarrhythmic effects by inhibiting the inward sodium current in cardiac cells, thus reducing the rate of increase in the cardiac action potential (phase 0) and decreasing automaticity in Purkinje fibers. This slows nerve impulses in the heart and stabilizes the heartbeat. The anesthetic activity is due to the ability of mexiletine to block sodium influx in peripheral nerves, thereby reducing the rate and intensity of pain impulses reaching the

Lidocaine relieves pain through non-specific blockage of sodium channels on ectopic periph‐ eral afferent fibers without causing numbness of the treated skin. Topical application without

vaccinia virus (Neurotropin®) as a first-line oral therapy[32].

synthase, resulting in the inhibition of nitric oxide synthesis [35].

20 years old and older and is very safe [32, 57, 58].

*3.5.4. Antiarrhythmics (mexiletine)*

CNS [41].

*3.5.5. Lidocaine patch 5%*

*3.5.3. Extract of cutaneous tissue from rabbits inoculated with vaccinia virus*

*3.5.1. Carbamazepine*

*3.5.2. Valproic acid*

In clinical practice, a combination of two or more drugs is often needed to achieve satisfactory pain relief, although few trials have been conducted to support this clinical observation. However, combination therapy with gabapentin or pregabalin and extended-release morphine in patients with PHN achieved higher pain relief with lower doses compared to administration of one drug alone. These results have also been confirmed for the combination of nortriptyline and gabapentin as well as for pregabalin and topical lidocaine in patients with PHN. Taken together, these results substantiate the usefulness of combination therapies in patients with PHN [9].
