Individualized Pharmacological Treatment of Neuropathic Pain SM Helfert1, M Reimer1, J H€ oper1 and R Baron1 Patients with the same disease may suffer from completely different pain symptoms yet receive the same drug treatment. Several studies elucidate neuropathic pain and treatment response in human surrogate pain models. They show promising results toward a patient stratification according to the mechanisms underlying the pain, as reflected in their symptoms. Several promising new drugs produced negative study results in clinical phase III trials. However, retrospective analysis of treatment response based on baseline pain phenotyping could demonstrate positive results for certain subgroups of patients. Thus, a prospective classification of patients according to pain phenotype may play an increasingly important role in personalized treatment of neuropathic pain states. A recent prospective study using stratification based on pain-related sensory abnormalities confirmed the concept of personalized pharmacological treatment of neuropathic pain.

INTRODUCTION

Pain does not equal pain – patients with pain because of damage of the nervous system may suffer from numerous, different, spontaneous, and evoked pain-related symptoms. Despite this heterogeneity of sensory abnormalities, the patients’ complaints are summarized under an umbrella diagnosis of “neuropathic pain syndrome” and they are treated according to the underlying disease entity and the overall pain intensity. In the last 20 years, various authors have claimed that this approach might not be successful and, as a new strategy, proposed a mechanism-based classification of neuropathic pain (i.e., grouping patients according to the mechanism of pain generation).1,2 These mechanisms are thought to be mirrored in the sensory signs and symptoms the patients express, the so-called “sensory phenotype.” Animal research has shown that different pathophysiological mechanisms in the central or peripheral nervous system can independently or in combination cause various symptoms. Clinical studies support the notion that similar mechanisms are involved in patients suffering from pain.3 Classifying pain according to the underlying mechanism should further help to establish an individualized pharmacological treatment of neuropathic pain, not only by identifying new therapeutic targets but also in describing which patients are likely to respond to a treatment.1,2 Within the last few years, a growing body of information has been generated about the mechanisms underlying pain

development. For example, it was shown that channels and receptors located on primary afferent nociceptors can be upregulated after nerve injury, causing abnormal sensitivity and spontaneous activity. This seems to be the case in spontaneous pain, shooting pain sensations, and heat hyperalgesia described by patients suffering from a form of neuropathic pain. Hypersensitivity to light touch or pinprick (i.e., mechanical or pinprick allodynia), occurs if input from mechanoreceptive A-fibers is felt as pain because of hyperexcitability of projection neurons in the spinal cord, a phenomenon called central sensitization.3–6 With all this knowledge, where do we stand today? A mechanism-based individualized treatment of neuropathic pain is still not part of a clinician’s daily routine. Nevertheless, progress has been made and, in this article, we aim to outline the current state of research in humans on the ambitious, yet promising path toward developing individualized pharmacological treatment of neuropathic pain (see Figure 1). Proof of concept: Studies in human surrogate models of neuropathic pain symptoms

Studying neuropathic pain, defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system,”7 in healthy humans represents an obvious challenge, there being ethical implications to consider, too. Nevertheless, several human surrogate models of neuropathic pain have been

1

Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital, Kiel, Germany. Correspondence: SM Helfert (s.helfert@ neurologie.uni-kiel.de) Received 11 September 2014; accepted 21 October 2014; advance online publication 00 Month 2014. doi:10.1002/cpt.19

CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014

1

Figure 1 Human trial designs for developing a mechanism-based therapy. Top: Human surrogate models help find new pain-generating mechanisms and develop new therapeutic agents. Middle: Assessing the pain phenotype at baseline and retrospective analysis of treatment responders and nonresponders. Bottom: Trial with different subgroups according to a patient stratification at baseline. VAS, Visual Analog Scale.

introduced8 to investigate the effect of different analgesics on various sensory signs and symptoms.9,10 In summary, there are electrical (continuous low-frequency electric stimulation, long-term potentiation models) and chemical models using topical or intradermal substances to activate specific receptors (e.g., topical and intradermal capsaicin, topical

menthol), thermal models (burn injury model, brief thermal sensitization model, freeze lesion), combined models (heat/capsaicin sensitization), and injury models that induce ethically acceptable mild injuries, such as the incision and sunburn models (NeuPSIG consensus meeting). In this article, we focus on the chemical models using capsaicin and menthol as they are widely

Table 1 Drug effects on symptoms induced by chemical human surrogate models Drug class NSAID

Spontaneous pain

Thermal hyperalgesia (heat/cold)

Punctate mechanical hyperalgesiaa

Dynamic mechanical allodynia

1*/1*

0*/1*; 0/1

1*/1*

1*/2*

16, 17* 45

0/2

0/2

18,19

References

TCA

0/2

NMDA receptor antagonists

4/8

0/2

3/8

1*/1*; 2/7

20* 21–27

Na-channel blocker: lidocaine

2/5

1/4

3/5

0/5

24,28–30

Na-channel blocker: lamotrigine

0/1

0/1

0/1

0/1

31

Ca-channel-blocker

1/3

0/1; 0/1

1/3

2/3

32–34 45

Opioids

4/6

0*/1*; 0/2; 1/2

0*/1*; 4/8; 0/1

0*/1*; 4/8; 0/1

36* 18, 25–27, 33, 35 36, 45

Cannabinoids

1/2

1/2

1/2

37,38

Ca, calcium; Na, sodium; NMDA, N-Methyl-D-Aspartate; NSAID, nonsteroidal anti-inflammatory drugs; TCA, tricyclic antidepressants. Overview of number of study arms in which drugs of different classes effectively reduced evoked symptoms out of studies in this drug class examining this symptom. Red with asterisk: studies using topical capsaicin model. Red: studies using intradermal capsaicin model. Blue: studies using topical menthol model. a Hyperalgesia to pinprick and von Frey filament stimuli. 2

VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary.com/cpt

established, simple to use, and not expensive. For a summary of pharmacological results in these models, see Table 1. Intradermal or topical capsaicin. Capsaicin, either applied topi-

cally on the skin or administered via intradermal injection, is commonly used as a model to study ongoing burning pain, heat hyperalgesia, dynamic mechanical allodynia, and pinprick hyperalgesia.11,12 It acts as a TRPV1 receptor agonist, causing peripheral and central sensitization. Allodynia and pinprick hyperalgesia are thus not only induced in the area in which capsaicin is administered (primary allodynia/hyperalgesia) but also in the surrounding area (secondary allodynia/hyperalgesia). Allodynia is usually tested with a cotton swab or brush, pinprick hyperalgesia using a pinprick or von Frey filament.13–15

that NMDA antagonists attenuate phenomena of central sensitization in the capsaicin-induced models via central mechanisms as only systemic, but not s.c. administration decreased the symptoms. Different doses might also cause differing results. One important limitation of the clinical use of NMDA antagonists are their pronounced side effects.10 Sodium channel blocker. Gottrup et al.

24

Nonsteroidal anti-inflammatory drugs. After topical capsaicin, Schmelz & Kress16 showed in 1996 that topical acetylsalicylate reduces both pain and secondary mechanical allodynia (assessed using a cotton swab) and hyperalgesia (von Frey filament), but not heat hyperalgesia. This effect on secondary allodynia/ hyperalgesia might be due to the decreased nociceptive afferent input. In contrast, Kilo et al.17 could not show an effect of ibuprofen on brush-evoked allodynia produced by topical capsaicin; here, it has been hypothesized that higher tissue concentrations might be needed.16

could show that lidocaine reduces the area of static hyperalgesia. This finding is in line with a trial by Koppert et al.28 showing a decreased area of pinprick hyperalgesia in the intradermal capsaicin model after infusing lidocaine, but no effect of lidocaine application in a regional anesthesia setting on pinprick hyperalgesia or mechanical allodynia, indicating a central antihyperalgesic mechanism of lidocaine. In contrast, a study by Wallace et al.29 did not find an effect of i.v. lidocaine on mechanical hyperalgesia and allodynia (von Frey hair, cotton wisp) but it reduced heat hyperalgesia. This discrepancy might be due to differing doses and timing.24 Ando et al.30 examined the effect of another sodium channel blocker, mexiletine (oral, titrated to a maximum of 1,350 mg/d or dose-limiting side effects), on intradermal capsaicin-induced symptoms and found a reduced area of static hyperalgesia (von Frey hair) but no effect on mechanical allodynia or heat hyperalgesia. For lamotrigine, no effect on intradermal capsaicin-evoked symptoms could be shown.31

Tricyclic antidepressants. For the tricyclic antidepressants ami-

Calcium channel blocker. Gottrup et al.

triptyline (25 mg amitriptyline i.m.) and desipramine (titrated to 300 mg or dose-limiting side effects), no effect could be shown on pain or secondary hyperalgesia induced by intradermal capsaicin. Tricyclic antidepressants not only act on descending pain pathways like the serotonergic and norepinephrinergic reuptake inhibitors but rather on several receptors, one mechanism being N-methyl-D-aspartate (NMDA) receptor blockade. The authors concluded that the lack of effect on capsaicin-induced hyperalgesia might suggest that the drugs examined had no or only weak NMDA antagonist properties.18,19 N-methyl-D-aspartate receptor antagonists. Using topical capsaicin, Desmeules et al.20 found a significantly decreased secondary mechanical allodynia (wooden rolling pin equipped with soft spurs) after blocking the NMDA receptor with dextromethorphan (50 mg orally). This finding could not be reproduced in the intradermal capsaicin model with 90 mg dextromethorphan orally.21 In contrast, Klein et al.22 also found a significant reduction in dynamic mechanical allodynia, but not pinprick secondary hyperalgesia, in the intradermal capsaicin model after a single dose of the NMDA receptor antagonist neramexane (40 mg orally). The NMDA antagonist ketamine reduces mechanical allodynia and punctate hyperalgesia induced by intradermal capsaicin when given i.v. but not s.c.23–25 Conflicting results were found regarding the time of administration: whereas Wallace et al.26 found no significant effect after capsaicin injection, Park et al.27 showed no effect of ketamine infused before capsaicin injection but a significant reduction of pinprick hyperalgesia when administering ketamine i.v. afterward. In summary, it seems CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014

32

also showed that oral gabapentin, titrated to 2,400 mg daily, diminishes the area of dynamic mechanical allodynia (cotton gauze) caused by intradermal capsaicin, while there was no significant reduction in pain intensity compared to placebo, indicating an effect mainly on central, but not peripheral sensitization. Wang et al.33 found a significant decrease in the area of secondary hyperalgesia (von Frey hair) produced by intradermal capsaicin after single doses of pregabalin (300 mg) and morphine (10 mg, i.v.) compared to active placebo. In contrast, Wallace et al.34 could not show an effect of gabapentin, titrated to 1,800 mg daily, in the intradermal capsaicin model. A possible explanation for this differing result might be a shorter period of sensory testing after capsaicin injection in the last study. Opioids. Two studies investigating the effect of alfentanil on symptoms induced by intradermal capsaicin showed a reduction in the area of hyperalgesia, this finding might be due to the decreased nociceptive input as they also found a reduction of overall pain.18,25 There is also conflicting evidence concerning the time of administration, in the aforementioned study by Wallace et al.,26 no effect of alfentanil when given after capsaicin injection was found, whereas Park et al.27 showed only an effect when giving alfentanil after capsaicin but not when administrating alfentanil preemptively. Investigating the effect of transdermal opioids on capsaicin-induced symptoms, Andresen et al.35 found no effect of buprenorphine or fentanyl transdermal patch. A recent prematurely terminated study evaluating the antihyperalgesic effect of tapentadol IR, a l-opioid receptor agonist and noradrenaline-reuptake inhibitor, on topical capsaicin-evoked 3

symptoms did not find a significant reduction in heat or mechanical hyperalgesia in the interims analysis (DGSS, Hamburg 2013).36 Cannabinoids. Examining the effect of smoked cannabis on symp-

toms evoked by intradermal capsaicin, Wallace et al.37 found that a medium dose (4% 9-d-tetrahydrocannabinol concentration) decreased spontaneous and evoked (stroking, von Frey hair) pain whereas a low dose (2%) did not differ from placebo, and a high dose (8%) actually increased pain. There was no effect on secondary allodynia/hyperalgesia at any dose. In contrast, Kraft et al.38 could not show any analgesic or antihyperalgesic effect of oral cannabis extract (20 mg 9-d-tetrahydrocannabinol). Discussing this discrepancy, they mentioned the possibility of ineffective blinding in a study of cannabis-experienced subjects smoking cannabis cigarettes. Topical menthol. Topical, highly concentrated (30–40%) menthol represents another interesting human surrogate model of neuropathic pain symptoms.39–41 Menthol is a TRPM8 receptor agonist42 that sensitizes cold-sensitive C nociceptors, causing cold and mechanical (pinprick) hyperalgesia. In addition to the hyperalgesia in the area of administration (primary hyperalgesia), menthol induces mechanical hyperalgesia (and inconsistently dynamic mechanical allodynia) in the surrounding area (secondary hyperalgesia) because of central sensitization caused by ongoing primary afferent nociceptor activity.39,41 Recently, it has been shown that menthol-evoked cold and mechanical hyperalgesia, but not the area of mechanical hyperalgesia, can be reproduced for an observation period of one week.43 Cold hyperalgesia develops frequently in patients with peripheral nerve injury, complex regional pain syndrome, or postherpetic neuralgia and is a characteristic symptom of oxaliplatin-induced polyneuropathy.43,44 In a study by Altis et al.,45 menthol-evoked cold hyperalgesia was induced in 20 healthy volunteers to investigate the analgesic effect of single doses of ibuprofen (600 mg), tramadol (100 mg), and pregabalin (100 mg). Tramadol significantly reduced menthol-evoked cold hyperalgesia, whereas the oral administration of pregabalin or ibuprofen did not lead to a significant decrease compared to placebo. With 100 mg tapentadol IR, no significant effect on the cold or mechanical hyperalgesia compared to placebo was found.36

Human surrogate models: Relevant in clinical practice?

Data generated in studies of the effect of different analgesics in the various human surrogate models can give important insight into the different mechanisms underlying these symptoms. However, there are several methodological shortcomings in some studies (i.e., lack of sufficiently addressing dose-response, active placebo, single vs. chronic dosing, and time-course of response from a single dose). Furthermore, it is essential that these models are used in a standardized way because different modes of dosing or administration may produce variable results, decreased sensitivity, and ultimately inconclusive and conflicting results.13 How relevant are these data from human experimental models for clinical use, though? In a review, Oertel & L€otsch46 examined 4

whether clinical analgesia could be predicted by using human surrogate pain models. They found that, in neuropathic pain states (pain from diabetic peripheral neuropathy, postherpetic neuralgia, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, or human immunodeficiency virus-associated peripheral neuropathy), the experimental pain condition that predicted analgesia for at least three drugs was chemical hyperalgesia in combination with punctate pressure (including capsaicin 1 von Frey hair, capsaicin 1 pinprick, and hypertonic saline 1 pinprick). It correctly predicted an analgesic effect of strong opioids and gabapentin as well as a lack of effect of lamotrigine. L€otsch et al.47 further examined agreement of drug efficacy between human models of pain and clinical studies, identifying four models predicting an analgesic effect in a large number of clinically relevant pain settings: chemical hyperalgesia 1 punctate pressure (capsaicin 1 von Frey hair/pinprick), UV-B induced hyperalgesia 1 contact heat, UV-B hyperalgesia 1 punctate pressure, and chemical pain (intranasal gaseous carbon dioxide). Nevertheless, the authors also support the further validation of other promising, biologically plausible models with little empirical information (e.g., the model of menthol-evoked cold hyperalgesia). In summary, experimental pain models in combination with pharmacological treatment can be used to study mechanisms of action of the drug, operating pain mechanisms, and the effect of the drug on specific sensory symptoms. However, results of these trials should not be used for go or no-go decisions in clinical drug development. Bringing pain patients into focus

The next important step in establishing an individualized, mechanism-based therapy is to prove that not only experimentally in healthy humans produced symptoms and signs but also patients classified into different mechanistic groups respond differently to pharmacological pain treatments. In order to analyze the different sensory abnormalities and combinations thereof – sensory patterns in patients – several tools are available. A standardized quantitative sensory testing (QST) protocol for clinical trials was introduced by the German Research Network on Neuropathic Pain (DFNS)48 in 2006 as standardization is crucial for comparing study results. Sensory stimuli are applied to the skin or deep somatic structures to elicit a painful or nonpainful sensation that can be quantified on a rating scale. QST uses a standardized battery of mechanical and thermal stimuli (graded vs. Frey hairs, several pinprick stimuli, pressure algometer, quantitative thermal testing, etc.) and assesses both negative signs (loss of function) and positive signs (gain of function) in the nociceptive and non-nociceptive afferent nervous systems. Based on this, a novel classification for neuropathic pain evolved, classifying patients according to loss or gain of function of their nerve fibers.44 There are additional possibilities for subgrouping patients regarding their sensory profile (e.g., patients showing signs of central sensitization because of the presence of dynamic or pinprick mechanical hyperalgesia). Another possibility to assess symptoms in neuropathic pain patients are patient-reported outcomes (questionnaires such as VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary.com/cpt

Douleur Neuropathique 4,49 PainDETECT Questionnaire (PDQ),50 and Neuropathic Pain Symptom Inventory (NPSI).51 Pain symptoms are evaluated directly by the patients and therefore can be used to phenotype them according to their perceived sensory abnormalities. In a study from 2009, Baron et al.52 found five distinct subgroups of sensory symptoms assessed with PDQ in 1623 patients with painful diabetic neuropathy and 498 patients with postherpetic neuralgia. In contrast to the QST, which evaluates stimulus-evoked sensations, questionnaires mainly assess spontaneous pain-related sensations, such as burning pain or prickling. Underlining the importance of phenotyping individuals to account for differences in pain response, another study examined heat and cold pain, pressure pain, ischemic pain, and temporal summation of heat pain in 291 healthy volunteers and evaluated the psychological and health-related data. The authors found five different clusters showing significant differences in somatic reactivity, catastrophizing, and demographics between the groups.53 A retrospective analysis of signs and symptoms of neuropathic pain patients at baseline in several studies demonstrates that patients with distinct underlying mechanisms respond differently to a certain therapy. In a double-blind, placebo-controlled study in 2004, Attal et al.54 found that dynamic or static mechanical allodynia assessed by QST seemed to be predictive of the response to i.v. administered lidocaine in 22 patients with pain because of traumatic nerve injury or postherpetic neuralgia. In 2006, Edwards et al.55 observed in 64 patients suffering from postherpetic neuralgia that the heat:pain threshold at baseline predicted the response to treatment with opioids but not to tricyclics or placebo. A study by Ranoux et al.56 examining the effect of intradermally injected botulinum A in 29 patients with postherpetic neuralgia or posttraumatic/postoperative neuropathy showed a correlation between the analgesic effect and preserved thermal sensibility at baseline, indicating intact cutaneous innervations. In 2005, Herrmann et al.57 investigated whether the epidermal innervation assessed with skin biopsy and QST or sensory nerve conduction studies in patients with diabetic and nondiabetic painful distal neuropathy predicted the treatment response to a 5% lidocaine patch. They hypothesized that patients with reduced epidermal innervation would respond less to this topical treatment, but they did not find a consistent association. In 2005, Wasner et al.,58 examining the association between the treatment response to topical lidocaine and function of thermosensitive and histamine-sensitive cutaneous afferents in patients with postherpetic neuralgia, even showed that there was a significant pain reduction in patients with impaired nociceptor function. Yarnitsky et al.59 investigated the association between the effect of duloxetine and pain modulation patterns in a study cohort of 30 patients with painful diabetic neuropathy. Under physiological conditions, pain is facilitated or inhibited by the monoaminergic descending pathways. The ability to activate these pathways varies among individuals; one means of assessing this capacity is by using the conditioned pain modulation protocol, measuring the pain reduction with QST during a simultaneously administered CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014

painful conditioning stimulus on a different part of the body.60,61 In the aforementioned study using this technique, Yarnitsky et al.59 showed that the conditioned pain modulation at baseline predicted the response to duloxetine, demonstrating a better response in patients with malfunctioning pain modulation. A large study conducted in 2010 by Simpson et al.62 in patients with human immunodeficiency virus-associated distal sensory polyneuropathy showed no efficacy of pregabalin. Nevertheless, a posthoc exploratory analysis was performed and showed that a subgroup of patients with an increased sensitivity to pinprick stimuli presented with significant improvement under the treatment with pregabalin. Freeman et al.63 published a post-hoc analysis based on data from four large studies examining the effect of pregabalin in patients with (1) central poststroke pain, (2) posttraumatic peripheral pain, (3) painful human immunodeficiency virus neuropathy, and (4) painful diabetic peripheral neuropathy. Retrospective cluster analysis of NPSI items from baseline assessment identified five subgroups of different pain-related characteristics and revealed that patients in three subgroups experienced greater pain improvement with pregabalin than with placebo. Using the entire study population, three of the four studies failed to prove a significant treatment effect of pregabalin vs. placebo at endpoint.64 Campbell et al.65 investigated treatment with topical clonidine in 179 patients with painful diabetic neuropathy in a randomized, placebo-controlled study. During screening, the nociceptor function had been assessed by the capsaicin challenge test, an increase in spontaneous pain after cutaneously administered capsaicin indicating intact and possibly sensitized nociceptors. No significant different pain reduction (primary endpoint) was found between clonidine and placebo in the intent-to-treat population, but a post-hoc analysis using the nociceptor function as stratification criterion revealed a significant pain reduction in the subgroup with functioning and presumably sensitized nociceptors. Martinez et al.66 evaluated the efficacy of perioperative administered minocycline, a microglial inhibitor, for decreasing persisting pain after lumbar discectomy in 100 patients and did not find any significant positive response. Interestingly, a post-hoc analysis showed a significant improvement in a subgroup of patients scoring 3 in the dimension “deep spontaneous pain” in the NPSI at baseline. Kalliom€aki et al.67 examined the efficacy of a chemokine receptor 2 antagonist, AZD2423, in 133 patients suffering from posttraumatic neuralgia. They did not find a significant difference between AZD2423 and placebo in the change in average pain scores (primary efficacy variable) but both the total NPSI score and its subscores for paresthesia/dysesthesia and paroxysmal pain tended to decrease more under the treatment with AZD2423. A study by H€oper et al.68 investigating the relation between the response to topical treatment with capsaicin 8% patches in patients with peripheral neuropathic pain and their symptoms, as assessed by PDQ at baseline could only show weak associations between pain reduction and high PDQ scores, burning pain, and pressure-evoked pain, respectively. Steigerwald et al.69 analyzed the efficacy of tapentadol in patients with severe, chronic, low back pain with a neuropathic pain component (probability “positive” or “unclear” in the PDQ; 5

N 5 126) or without it (probability “negative” in the PDQ; N 5 49). Average pain intensity (primary endpoint) was significantly reduced; it could also be shown that in patients with a neuropathic pain component that the neuropathic pain symptoms, number of pain attacks, and spontaneous pain duration improved significantly. Recently, Bouhassira et al.70 published data from an exploratory post-hoc analysis of a study examining the effect of highdose duloxetine or pregabalin monotherapy vs. a combination of duloxetine and pregabalin in patients with painful diabetic neuropathy. They could show that patients in whom average pain did not improve 30% after an eight-week period of treatment with 60 mg duloxetine showed greater improvement in the dimensions “pressing pain” and “evoked pain” assessed by NPSI when adding 300 mg pregabalin, whereas there was a greater benefit in the dimension “paresthesia/dysesthesia” of NPSI when treated with 120 mg duloxetine. In patients with no adequate treatment response after eight weeks of 300 mg pregabalin, NPSI score changes were greater using combination therapy (300 mg pregabalin 1 60 mg duloxetine) than high-dose pregabalin monotherapy (600 mg pregabalin), but the differences were smaller between therapies than in patients treated with duloxetine in the initial period. Three clusters could be identified, with different pain profiles showing a nonsignificant trend toward a better treatment effect of high-dose monotherapy in one cluster with patients reporting higher intensity of average pain and NPSI items, whereas patients in the other clusters with mild to moderate pain seemed to benefit more from combination therapy. A study recently presented as a poster showed a different efficacy of the therapy with intra-articular onabotulinumtoxin-A in patients stratified in a post-hoc analysis using the PDQ. Although this study was conducted in patients with osteoarthritis, which is not a classical neuropathic pain state, it demonstrated that treatment success was different after stratifying patients according to their pain phenotype. The subgroup with nociceptive pain (PDQ score 12) showed a numerically greater improvement after onabotulinumtoxin-A compared to placebo in the primary outcome (14-day average daily pain score).71,72 A look into the future: Prospective studies using mechanismbased classification

Post-hoc stratification according to the sensory profile or sensory phenotype showed promising results for subgroups of patients. As a further step toward developing individualized pharmacological treatment of neuropathic pain, studies prospectively stratifying patients according to their sensory symptoms and signs are needed.73 Recently, Demant et al.74 examined in a randomized, doubleblinded, placebo-controlled trial the pain-relieving effect of oxcarbazepine in 72 patients with postherpetic neuralgia, surgical or traumatic nerve injury, or polyneuropathy. They performed QST at the beginning of the trial and stratified the patients according to their sensory profile into one of two groups: (1) “irritable nociceptor” with predominantly a “gain of function” and a preserved small-fiber nerve function and (2) “deafferentation type” dominated by sensory loss. This stratification is based on the 6

assumption that ectopic activity from upregulated sodium channels is mainly responsible for hyperalgesia (“irritable nociceptor”) and therefore oxcarbazepine, a sodium channel blocker, should have an effect in these patients. Although oxcarbazepine is recommended as first-line therapy for trigeminal neuralgia, it only plays a minor role in the treatment of other neuropathic pain syndromes because of controversial study results.75 This study showed positive results and a treatment response depending on the sensory phenotype. For all patients, the number-needed-to-treat for a 50% pain relief was 6.9; the number-needed-to-treat in the group with the “irritable nociceptor phenotype” was only 3.9; whereas for the “nonirritable nociceptor” phenotype of the number-needed-to-treat was 13.74 SUMMARY

Tremendous progress has been made in the last decade in our understanding of different pain-generating mechanisms. In this article, we demonstrated possibilities of examining these paingenerating mechanisms in human surrogate models and of developing new therapeutic targets. Quantitative sensory testing is a promising diagnostic tool to identify appropriate subgroups of patients based on their sensory profile. However, further, simpler bedside QST techniques that can be applied more easily in general practice need to be developed. Alternatively, patient-reported outcomes should be improved and applied in pharmacological trials. As a crucial last step for developing individualized therapy for neuropathic pain and to ultimately integrate this concept into general practice, clinical trials are needed in which patients are stratified at baseline. Initial studies clearly support the idea of a mechanism-based, individualized therapy for neuropathic pain patients and provide hope that we are on the right track. CONFLICT OF INTEREST S.M.H. has received speaking fees or research support from Astellas, €nenthal, and Pfizer. J.H. has received speaking fees or Genzyme, Gru €nenthal, Astellas, and Genzyme. M.R. research support from Pfizer, Gru €nenthal, Astelhas received speaking fees or research support from Gru las, and Pfizer. R.B. is a member of the IMI Europain consortium, IMI “Europain” collaboration and industry members are: Astra Zeneca, Pfizer, €nenthal, Eli Lilly, and Boehringer Esteve, UCB-Pharma, Sanofi Aventis, Gru Ingelheim. He has received grants/research support from the German Federal Ministry of Education and Research (BMBF) (German Research Network on Neuropathic Pain, NoPain system biology), the German €nenthal. He has Research Foundation (DFG), Pfizer, Genzyme, and Gru €nenthal, Mundipharma, received speaking fees from Pfizer, Genzyme, Gru Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva Pharma, Bayer-Schering, and MSD. He has been a consul€nenthal, Mundipharma, Allergan, Sanofi Pastant to Pfizer, Genzyme, Gru teur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Novartis, Bristol-Myers Squibb, Biogenidec, AstraZeneca, Merck, Daiichi, and Abbvie.

ACKNOWLEDGMENTS €nenthal GmbH. This research was made possible by the support of Gru We thank Sherryl Sundell for language editing. C 2014 American Society for Clinical Pharmacology and Therapeutics V

VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary.com/cpt

1. 2. 3.

4.

5.

6. 7.

8. 9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

Max, M.B. Towards physiologically based treatment of patients with neuropathic pain. Pain 42, 131–137 (1990). Woolf, C.J. et al. Towards a mechanism-based classification of pain? Pain 77, 227–229 (1998). von Hehn, C.A., Baron, R. & Woolf, C.J. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 73, 638–652 (2012). Lai, J., Hunter, J.C. & Porreca, F. The role of voltage-gated sodium channels in neuropathic pain. Curr. Opin. Neurobiol. 13, 291–297 (2003). Siqueira, S.R., Alves, B., Malpartida, H.M., Teixeira, M.J. & Siqueira, J.T. Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia. Neuroscience 164, 573– 577 (2009). Woolf, C.J. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152(3 suppl), S2–S15 (2011). Treede, R.D. et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70, 1630–1635 (2008). Klein, T., Magerl, W., Rolke, R. & Treede, R.D. Human surrogate models of neuropathic pain. Pain 115, 227–233 (2005). Staahl, C., Olesen, A.E., Andresen, T., Arendt-Nielsen, L. & Drewes, A.M. Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review. Br. J. Clin. Pharmacol. 68, 149–168 (2009). Staahl, C., Olesen, A.E., Andresen, T., Arendt-Nielsen, L. & Drewes, A.M. Assessing efficacy of non-opioid analgesics in experimental pain models in healthy volunteers: an updated review. Br. J. Clin. Pharmacol. 68, 322–341 (2009). Simone, D.A., Baumann, T.K. & LaMotte, R.H. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 38, 99–107 (1989). €rk, H.E. Pain, hyperalgesia LaMotte, R.H., Lundberg, L.E. & Torebjo and activity in nociceptive C units in humans after intradermal injection of capsaicin. J. Physiol. 448, 749–764 (1992). Liu, M., Max, M.B., Robinovitz, E., Gracely, R.H. & Bennett, G.J. The human capsaicin model of allodynia and hyperalgesia: sources of variability and methods for reduction. J. Pain Symptom Manage. 16, 10– 20 (1998). Hughes, A., Macleod, A., Growcott, J. & Thomas, I. Assessment of the reproducibility of intradermal administration of capsaicin as a model for inducing human pain. Pain 99, 323–331 (2002). Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D. & Julius, D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997). Schmelz, M. & Kress, M. Topical acetylsalicylate attenuates capsaicin induced pain, flare and allodynia but not thermal hyperalgesia. Neurosci. Lett. 214, 72–74 (1996). Kilo, S., Forster, C., Geisslinger, G., Brune, K. & Handwerker, H.O. Inflammatory models of cutaneous hyperalgesia are sensitive to effects of ibuprofen in man. Pain 62, 187–193 (1995). Eisenach, J.C., Hood, D.D., Curry, R. & Tong, C. Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans. Anesthesiology 86, 1279–1287 (1997). Wallace, M.S., Barger, D. & Schulteis, G. The effect of chronic oral desipramine on capsaicin-induced allodynia and hyperalgesia: a double-blinded, placebo-controlled, crossover study. Anesth. Analg. 95, 973–978 (2002). Desmeules, J.A., Oestreicher, M.K., Piguet, V., Allaz, A.F. & Dayer, P. Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan. J. Pharmacol. Exp. Ther. 288, 607– 612 (1999). Kinnman, E., Nygårds, E.B. & Hansson, P. Effects of dextromethorphan in clinical doses on capsaicin-induced ongoing pain and mechanical hypersensitivity. J. Pain Symptom Manage. 14, 195–201 (1997). Klein, T., Magerl, W., Hanschmann, A., Althaus, M. & Treede, R.D. Antihyperalgesic and analgesic properties of the N-methyl-D-aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic hyperalgesia. Eur. J. Pain 12, 17–29 (2008). Gottrup, H., Bach, F.W., Arendt-Nielsen, L. & Jensen, T.S. Peripheral lidocaine but not ketamine inhibits capsaicin-induced hyperalgesia in humans. Br. J. Anaesth. 85, 520–528 (2000).

CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014

24. Gottrup, H., Hansen, P.O., Arendt-Nielsen, L. & Jensen, T.S. Differential effects of systemically administered ketamine and lidocaine on dynamic and static hyperalgesia induced by intradermal capsaicin in humans. Br. J. Anaesth. 84, 155–162 (2000). 25. Wallace, M.S., Ridgeway, B. 3rd, Leung, A., Schulteis, G. & Yaksh, T.L. Concentration-effect relationships for intravenous alfentanil and ketamine infusions in human volunteers: effects on acute thresholds and capsaicin-evoked hyperpathia. J. Clin. Pharmacol. 42, 70–80 (2002). 26. Wallace, M.S., Braun, J. & Schulteis, G. Postdelivery of alfentanil and ketamine has no effect on intradermal capsaicin-induced pain and hyperalgesia. Clin. J. Pain 18, 373–379 (2002). 27. Park, K.M., Max, M.B., Robinovitz, E., Gracely, R.H. & Bennett, G.J. Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects. Pain 63, 163–172 (1995). 28. Koppert, W., Ostermeier, N., Sittl, R., Weidner, C. & Schmelz, M. Lowdose lidocaine reduces secondary hyperalgesia by a central mode of action. Pain 85, 217–224 (2000). 29. Wallace, M.S., Laitin, S., Licht, D. & Yaksh, T.L. Concentration-effect relations for intravenous lidocaine infusions in human volunteers: effects on acute sensory thresholds and capsaicin-evoked hyperpathia. Anesthesiology 86, 1262–1272 (1997). 30. Ando, K., Wallace, M.S., Braun, J. & Schulteis, G. Effect of oral mexiletine on capsaicin-induced allodynia and hyperalgesia: a doubleblind, placebo-controlled, crossover study. Reg. Anesth. Pain Med. 25, 468–474 (2000). 31. Wallace, M.S., Quessy, S. & Schulteis, G. Lack of effect of two oral sodium channel antagonists, lamotrigine and 4030W92, on intradermal capsaicin-induced hyperalgesia model. Pharmacol. Biochem. Behav. 78, 349–355 (2004). 32. Gottrup, H. et al. Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology 101, 1400–1408 (2004). 33. Wang, H. et al. Effect of morphine and pregabalin compared with diphenhydramine hydrochloride and placebo on hyperalgesia and allodynia induced by intradermal capsaicin in healthy male subjects. J. Pain 9, 1088–1095 (2008). 34. Wallace, M.S. & Schulteis, G. Effect of chronic oral gabapentin on capsaicin-induced pain and hyperalgesia: a double-blind, placebo-controlled,crossover study. Clin. J. Pain 24, 544–549 (2008). 35. Andresen, T., Staahl, C., Oksche, A., Mansikka, H., Arendt-Nielsen, L. & Drewes, A.M. Effect of transdermal opioids in experimentally induced superficial, deep and hyperalgesic pain. Br. J. Pharmacol. 164, 934–945 (2011). €rster, M. et al. TapCapMentho – a double-blinded, placebo36. Fo controlled, cross-over phase I study for evaluation of the effect of 100mg tapentadol IR in two models of thermal and mechanical hyperalgesia. Der Schmerz 27, 1–137 (2013). 37. Wallace, M. et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 107, 785–796 (2007). 38. Kraft, B. et al. Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Anesthesiology 109, 101–110 (2008). 39. Wasner, G., Schattschneider, J., Binder, A. & Baron, R. Topical menthol--a human model for cold pain by activation and sensitization of C nociceptors. Brain 127(Pt 5), 1159–1171 (2004). 40. Hatem, S., Attal, N., Willer, J.C. & Bouhassira, D. Psychophysical study of the effects of topical application of menthol in healthy volunteers. Pain 122, 190–196 (2006). 41. Binder, A., Stengel, M., Klebe, O., Wasner, G. & Baron, R. Topical high-concentration (40%) menthol-somatosensory profile of a human surrogate pain model. J. Pain 12, 764–773 (2011). 42. McKemy, D.D., Neuhausser, W.M. & Julius, D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58 (2002). €llemann, P., Wasner, G., Baron, R. & Binder, A. Topical 43. Mahn, F., Hu high-concentration menthol: reproducibility of a human surrogate pain model. Eur. J. Pain, 18, 1248–1258 (2014). 44. Maier, C. et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities 7

45.

46.

47. 48.

49.

50.

51. 52.

53.

54.

55.

56.

57.

58.

59. 60.

61.

8

in 1236 patients with different neuropathic pain syndromes. Pain 150, 439–450 (2010). Altis, K. et al. Analgesic efficacy of tramadol, pregabalin and ibuprofen in menthol-evoked cold hyperalgesia. Pain 147, 116–121 (2009). €tsch, J. Clinical pharmacology of analgesics Oertel, B.G. & Lo assessed with human experimental pain models: bridging basic and clinical research. Br. J. Pharmacol. 168, 534–553 (2013). €tsch, J., Oertel, B.G. & Ultsch, A. Human models of pain for the preLo diction of clinical analgesia. Pain 155, 2014–2021 (2014). Rolke, R. et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123, 231–243 (2006). Bouhassira, D. et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 114, 29–36 (2005). €lle, T.R. painDETECT: a Freynhagen, R., Baron, R., Gockel, U. & To new screening questionnaire to identify neuropathic components in patients with back pain. Curr. Med. Res. Opin. 22, 1911–1920 (2006). Bouhassira, D. et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 108, 248–257 (2004). €lle, T.R., Gockel, U., Brosz, M. & Freynhagen, R. A crossBaron, R., To sectional cohort survey in 2100 patients with painful diabetic neuropathy and postherpetic neuralgia: differences in demographic data and sensory symptoms. Pain 146, 34–40 (2009). Cruz-Almeida, Y., Riley, J.L. 3rd & Fillingim, R.B. Experimental pain phenotype profiles in a racially and ethnically diverse sample of healthy adults. Pain Med. 14, 1708–1718 (2013). Attal, N., Rouaud, J., Brasseur, L., Chauvin, M. & Bouhassira, D. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology 62, 218–225 (2004). Edwards, R.R., Haythornthwaite, J.A., Tella, P., Max, M.B. & Raja, S. Basal heat pain thresholds predict opioid analgesia in patients with postherpetic neuralgia. Anesthesiology 104, 1243–1248 (2006). Ranoux, D., Attal, N., Morain, F. & Bouhassira, D. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann. Neurol. 64, 274–283 (2008). Herrmann, D.N., Pannoni, V., Barbano, R.L., Pennella-Vaughan, J. & Dworkin, R.H. Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies. Muscle Nerve 33, 42–48 (2006). Wasner, G., Kleinert, A., Binder, A., Schattschneider, J. & Baron, R. Postherpetic neuralgia: topical lidocaine is effective in nociceptordeprived skin. J. Neurol. 252, 677–686 (2005). Yarnitsky, D. et al. Recommendations on terminology and practice of psychophysical DNIC testing. Eur. J. Pain 14, 339 (2010). Bannister, K., Bee, L.A. & Dickenson, A.H. Preclinical and early clinical investigations related to monoaminergic pain modulation. Neurotherapeutics 6, 703–712 (2009). Yarnitsky, D., Granot, M., Nahman-Averbuch, H., Khamaisi, M. & Granovsky, Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain 153, 1193–1198 (2012).

62. Simpson, D.M. et al. Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology 74, 413–420 (2010). 63. Freeman, R., Baron, R., Bouhassira, D., Emir, B., Cheung, R. & Murphy, K. Identification of sensory symptom clusters in patients with neuropathic pain based on the neuropathic pain symptom inventory questionnaire. Pain 12, 48 (2011). 64. Freeman, R., Baron, R., Bouhassira, D., Cabrera, J. & Emir, B. Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs. Pain 155, 367–376 (2014). 65. Campbell, C.M. et al. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain 153, 1815–1823 (2012). 66. Martinez, V. et al. The efficacy of a glial inhibitor, minocycline, for preventing persistent pain after lumbar discectomy: a randomized, double-blind, controlled study. Pain 154, 1197–1203 (2013). €ki, J. et al. A randomized, double-blind, placebo-controlled 67. Kallioma trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. Pain 154, 761–767 (2013). €per, J., Helfert, S., Heskamp, M.L., Maiho €fner, C.G. & Baron, R. 68. Ho High concentration capsaicin for treatment of peripheral neuropathic pain: effect on somatosensory symptoms and identification of treatment responders. Curr. Med. Res. Opin. 30, 565–574 (2014). 69. Steigerwald, I. et al. Effectiveness and safety of tapentadol prolonged release for severe, chronic low back pain with or without a neuropathic pain component: results of an open-label, phase 3b study. Curr. Med. Res. Opin. 28, 911–936 (2012). 70. Bouhassira, D. et al. Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: data from the randomized, double-blind, COMBO-DN study. Pain 155, 2171–2179 (2014). 71. Kalunian, K.C., Arendt-Nielsen, L., Turkel, C.C. & DeGryse, R. Results from a single center, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy and safety of intra-articular onabotulinumtoxina for osteoarthritis knee pain. Osteoarthritis Cartilage 22, S57–S489 (2014). 72. Arendt-Nielsen, L., Jiang, G.-L., DeGryse, R. & Turkel, C.C. A single center, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy and safety of intra-articular onabotulinumtoxina as treatment for osteoarthritis knee pain: results from the experimental pain models. Osteoarthritis Cartilage 22, S7–S56 (2014). 73. Reimer, M., Helfert, S.M. & Baron, R. Phenotyping neuropathic pain patients: implications for individual therapy and clinical trials. Curr. Opin. Support. Palliat. Care 8, 124–129 (2014). 74. Demant, D.T. et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. Pain (in press). 75. Attal, N. et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur. J. Neurol. 17, 1113–e88 (2010).

VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary.com/cpt