Expert opinion on emerging drugs: chronic low back pain.

Review

Expert opinion on emerging drugs: chronic low back pain

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Selcuk Universitesi on 12/24/14 For personal use only.

Eugene Hsu, Sunberri Murphy, David Chang & Steven P Cohen† †

Johns Hopkins School of Medicine and Uniformed Services University of the Health Sciences, Bethesda, MD, USA

1.

Background

2.

Medical need

3.

Existing treatments

4.

Market review

5.

Current research goals

6.

Scientific rationale for mechanism-based treatment of LBP

7.

Competitive environment

8.

Potential development issues

9.

Conclusions

10.

Expert opinion

Introduction: It is difficult to overestimate the personal and socioeconomic impact of chronic low back pain (CLBP). It is the leading cause of years lost to disability and poses the highest economic toll among chronic illnesses. Despite the strong need for extensive research efforts, few drugs have consistently demonstrated effectiveness for this condition. Areas covered: In this review, the epidemiology, rationale for mechanismbased treatment, competitive environment and market trends, and the preclinical and clinical evidence supporting over 15 different classes of analgesic medications studied for CLBP or related pain conditions are discussed. Treatments are divided by drug category, type of CLBP they are likely to treat (e.g., neuropathic or mechanical), and whether they are new formulations of existing treatments, new indications for existing treatments or represent novel mechanisms of action. Databases searched included MEDLINE, Embase, Pharmaprojects and various clinical trial registries. Expert opinion: Many barriers exist for the development of medications for CLBP including difficulties in identifying pathophysiological mechanisms, biologic resiliency secondary to multiple concurrent pain pathways and offtarget and sometimes serious side effects. Nevertheless, the volume and diversity of novel molecular entities has continued to surge and includes possible disease-modifying therapies such as gene and stem cell therapy. Keywords: low back pain, mechanical back pain, mechanism-based treatment, pharmacotherapy, radiculopathy, sciatica Expert Opin. Emerging Drugs [Early Online]

1.

Background

One would be hard-pressed to overestimate the societal and economic tolls exacted by low back pain (LBP). LBP is the leading cause of disability in the world, with a lifetime prevalence rate ranging between 50 and 90% [1-3]. In the US alone, the annual cost of LBP by some estimates exceeds $100 billion, with over one-half stemming from lost productivity [3-5]. LBP is sometimes considered to be a ‘diagnosis’ but is more accurately defined as a symptom characterized by multiple and often overlapping mechanisms. One of the most common classification schemes distinguishes LBP as being either neuropathic (pain caused by a disease or lesion affecting the somatosensory system) or nociceptive/mechanical pain (which is caused by peripheral stimulation of painful nerve endings embedded in structures contained within or supporting the lumbar spinal column such as muscles, intervertebral discs, facet joints, etc.) [6,7]. Although we will use this mechanism-based definition for the purpose of this review, it should be noted that several authors have emphasized a broader definition for chronic LBP (CLBP). Waddell was one of the first to utilize the biopsychosocial model, which postulates that biological, psychological and social factors all play a role in disease, as an operational model to assess the impact of physical rehabilitation approaches for CLBP [8].

10.1517/14728214.2015.993379 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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The treatment of pain, in general, and LBP, in particular, is notoriously challenging. Indeed, the effect sizes of most nonsurgical treatments for nonspecific LBP are low to moderate (0.2 -- 0.6) and unlikely to result in complete pain relief [9]. Therefore, pain management is aimed at reducing dysfunction in physical, psychological and social dimensions while improving quality of life for patients and minimizing risks and adverse effects. Studies have found a 30% pain reduction to constitute clinically meaningful benefit [10-13], but a decrease of as little as 10% compared to ‘placebo’ is what is often required for regulatory drug approval [14]. For acute LBP, the PACE study of paracetamol, a first-line analgesic, showed that scheduled or as needed paracetamol did not affect recovery time compared to placebo [15]. For neuropathic back pain, clinical trials evaluating first-line medications such as tricyclic antidepressants (TCAs) and gabapentinoids have generally found very small differences between treatment and control groups [16,17]. For CLBP, systematic reviews have found small effect sizes supporting NSAIDs, opioids and muscle relaxants, with mixed results for antidepressants [18-21]. The combination of the high prevalence rate and economic burden, manifold mechanisms and recalcitrance to treatment has led to an onslaught of research aimed at alleviating LBP. Whereas the purpose of this review is to evaluate emerging pharmacologic therapies for LBP based on clinical trials, the important role of physical, psychological and rehabilitation treatments cannot be understated [22]. 2.

Medical need

There is a strong need for new and novel treatments for CLBP, as existing treatments have shown very modest efficacy and tend to be characterized by significant side effects, risks and costs. Moreover, despite the multiple pharmacological and non-pharmacological treatments that have emerged over the past two decades, the number of patients reporting LBP [23,24] and disability claims have continued to rise [25]. Over the past decade, there have been concomitant increases in sales of prescription and illicit (i.e., diversion) opioid medications with a trend toward more potent opioids, as well as deaths from prescription drugs [26-28]. The 2011 Centers for Disease Control and Prevention Morbidity and Mortality Report estimates that there were 20,044 deaths due to prescription drugs in 2008, with 73% due to opioids [28]. In a systematic review and treatment guideline for CLBP published by the American Pain Society (APS), Chou and Huffman reviewed 40 pharmacological randomized controlled trials (RCTs) with just one recommendation based on ‘good evidence’, namely TCAs are moderately more effective than placebo for CLBP. The APS review underscores the great need for safe, effective and non-addictive analgesics [29]. 3.

Existing treatments

Multiple interventions including physical therapy, psychological therapy, injection therapy, surgery and multimodality 2

therapy are used to treat CLBP [30,31]. Although not the focus of this review, it should be emphasized that the evidence for multimodal treatment programs shows significant reduction in pain and prescription drug use, healthcare resources and income support, and an increase in rates of people who return to work. Injections tend to provide only short- or intermediate-term relief to a subset of individuals, and in some instances it may be associated with catastrophic complications [11,32,33]. Most randomized studies of decompression surgery for neurogenic LBP have shown benefit for shortterm (< 1 year) but not long-term (> 2 years) relief [34,35] and most randomized studies of fusion or disc replacement surgery suggest than less than one-third of people can expect clinically meaningful pain relief or functional improvement with the benefits diminishing over time [36]. Psychological and physical and rehabilitation approaches have been shown to provide modest treatment effects in two Cochrane reviews and will not be discussed here [37,38]. Duloxetine is the only non-opioid analgesic to receive FDA approval for the treatment of mechanical LBP, yet clinical trials have shown only modest (£ 1-point) improvement compared to placebo [14,39], and one systematic review found no significant difference between duloxetine and other oral pharmacotherapeutics [40]. A recent responder analysis conducted by Moore et al. demonstrated that patients with CLBP receiving duloxetine responded in a bimodal fashion, experiencing either very good or very poor pain relief [41]. There are currently no drugs approved for neurogenic LBP.

4.

Market review

The overall global market for pain therapeutics grew at a compounded annual growth rate (CAGR) of 5.3% between 2002 and 2010 to an estimated market size of $28.6 billlion [42]. The top eight therapeutic indications by annual sales for pain therapies included postoperative pain, LBP, neuropathic pain, fibromyalgia, osteoarthritis (OA) pain, rheumatoid arthritis pain, cancer pain and migraines. Of these indications, LBP accounted for ~ 17% of the worldwide pain management therapeutics market with $4.9 billion in annual sales [42]. Despite impending patent expirations of the two top selling agents for neuropathic pain (pregabalin with $4.595 billion in annual sales for all indications in 2013 and duloxetine with $5.084 billion in annual sales for all indications in 2013), the expected ‘blockbuster’ sales for new pain drugs have not been realized [43,44]. For example, tapentadol, a µ-opioid agonist and norepinephrine reuptake inhibitor, obtained FDA approval for diabetic peripheral neuropathy in 2011, but annual sales in 2013 are still relatively small at $86 million [45]. The overall market is expected to grow more slowly in the next few years at a CAGR of 3.84%, with a forecast to be ~ $35 billion in size by 2017 [42].

Expert Opin. Emerging Drugs (2014) 20(1)



Glial cell antagonists lon channel antagonists

α-2 agonists Bisphosphonates Cytokine inhibitors Gene therapy NGF antagonists NMDA antagonists Opioid agonists ORL-1 agonists PDE inhibitors SNRI, SDRI Stem cell therapy TLR antagonists TRPV1 modulators

NSAIDs

Nociceptive pain Neuropathic pain

Figure 1. Venn diagram showing analgesic class by mechanism of action. NGF: Nerve growth factor; NMDA; N-methyl-D-aspartate; NSAID: Nonsteroidal anti-inflammatory drug; ORL: Opioid receptor like; PDE: Phosphodiesterase inhibitor; SDRI: Serotonin-Dopamine reuptake inhibitor; SNDRI: Serotonin-Norepinephrine-Dopamine reuptake inhibitor; SNRI: Serotonin-Norepinephrine reuptake inhibitor; TLR: Toll-like receptor.

5.

Current research goals

Current research goals include discovering and identifying medications with improved efficacy, longer duration of action and fewer side effects and unwanted sequelae such as addiction. Patients with CLBP could benefit both from the development of novel treatments targeting specific mechanisms as well as diagnostic and prognostic tools for proper risk stratification and personalized therapy. Finally, further study of the underlying pathogenesis of CLBP could better enable the development of disease-modifying therapies.

Scientific rationale for mechanism-based treatment of LBP

6.

About 15 years ago, in a review published in the New England Journal of Medicine, Deyo and Weinstein estimated that neuropathic pain comprised < 10% of LBP [46]. In the intervening years, several instruments have been published that facilitate classification of pain into neuropathic, nociceptive and mixed [7,47]. Multiple studies have since been published using these instruments to categorize CLBP patients into neuropathic or nociceptive and have found that neuropathic pain accounts for between 17 and 55% of cases, with a median rate of around 41% [6,7,10,11]. The distinction is important because it affects treatment decisions at all levels of care (e.g., pharmacotherapy, type of injection or surgery) (Figures 1 and 2)

It is widely acknowledged that the mechanism-based treatment of pain is superior to etiologic or disease-based treatments, yet in practice this is difficult to implement [12]. Identifying the precise mechanism(s) can be challenging, if not impossible. For example, intravenous infusion tests have been used for nearly 20 years as tools to identify pain mechanisms and guide treatment, but these tests generally suffer from low specificity and indeterminate sensitivity and at best have marginal predictive value [48]. Many treatments considered to be effective only for neuropathic pain such as gabapentinoids have proven to be beneficial for nociceptive pain [49], and drugs designed and tested primarily for nociceptive pain such as NSAIDs have shown efficacy for neuropathic pain [50,51]. Part of the reason for this is that there is considerable overlap in pain mechanisms such that the taxonomic classification of pain may bear little relationship to clinical considerations. Consequently, many experts consider it more practical to consider the various types of pain as different points on the same continuum rather than distinct entities [6]. 7.

Competitive environment

A search for compounds in development for CLBP was performed on the clinicalTrials.gov clinical trials registry. Additional developmental compounds were identified through database search of keywords relating to therapeutic targets for the treatment of CLBP (Pharmaprojects, MEDLINE, Embase, Google Scholar). Keyword search terms were


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Cortex

Pain perception and amplification: • Placebo Descending modulation: • Anti-depressants • Opioids, tramadol • Muscle relaxants • Cannabinoids


Thalamus

Synaptic transmission and central sensitization: • Anti-convulsants • α2 adrenegic agonists • Opioids • NMDA blockers (e.g., ketamine) • Nerve growth factor inhibitors • Cytokine inhibitors • Muscle relaxants • Cannabinoids

PAG

RVM

Peripheral stimulation,transduction, transmission and amplification: • Anti-inflammatory drugs • Topical agents • Anti-convulsants • Cytokine inhibitors • Anti-depressants • Nerve growth factor inhibitors • Cannabinoids

Figure 2. Illustration showing the site(s) of action of various classes of analgesics. Adapted from [6] drawing by Shizuka Aoki. PAG: Periaqueductal gray; RVM: Rostral ventromedial medulla.

identified from the current understanding of mechanisms involved in pain processing. Results were limited to compounds in Phase II or Phase III of development, which were classified based on whether they were new formulations of existing compounds, new indications for existing compounds or represented novel mechanisms of action (Tables 1, 2 and 3). Each compound is categorized by its mechanistic contribution to either nociceptive or neuropathic pain (Figure 1).

New formulations of existing compounds Perhaps in an effort to minimize the enormous cost and risk associated with developing novel compounds, most new pain therapeutics approved in recent years are new formulations of existing drugs [52]. New formulations can be subdivided into 7.1

4

novel delivery mechanisms and formulations designed to improve the safety profile of known adverse effects. The latter approach highlights recent actions by the FDA emphasizing drug safety. In 2007, the FDA Amendments Act granted the FDA the authority to decide when to require a Risk Evaluation and Mitigation Strategy (REMS) from drug sponsors [53]. REMS are risk management programs that use risk minimization strategies to ensure that the benefits of a drug outweigh its risks. Each REMS contains specific measures unique to the safety risks associated with a particular drug or class of drugs. In response to the alarming increase in opioid prescriptions and opioid-related overdose deaths, in February 2009, the FDA began requiring manufacturers of high-risk opioids to incorporate REMS to address abuse, misuse and exposure of non-opioid-tolerant persons to opioids [28,54,55]. In 2012, the FDA approved a



Nociceptive pain, neuropathic pain

Pre-registration FDA has accepted for filing the NDA for MNK-155) n = 155 RCT; n = 52

Route of administration

Study design

COX-1 inhibitor COX-2 inhibitor Opioid d-receptor agonist Opioid k-receptor agonist opioid µ-receptor agonist

Sodium channel antagonist

Oral

Transdermal

Intranasal

6h

12 wk

12 wk

Follow-up period

12 wk

Single-center, randomized, double-blind,

N/A

Open-label, single-group- 5 wk assignment study in patients with OA of the knee or hip or moderateto-severe CLBP

Randomized, doubleblind, placebo-controlled in patients with CLBP

Randomized, doubleN/A blind, placebo-controlled, three-period, crossover study in patients with CLBP

Randomized, doubleblind, placebo-controlled in opioid-experienced subjects with CLBP Randomized, doubleblind, placebo-controlled in opioid-naı¨ve subjects with moderate-to-severe CLBP requiring opioid analgesia. a2 adrenoreceptor Oral, spray Oral, Double-blind, placeboagonist sublingual controlled, crossover study in patients with CLBP

Opioid k-receptor Oral, buccal antagonist, Opioid soluble film µ-receptor agonist/ antagonist, ORL 1 agonist

Mechanism of action

Both intact and crushed MNK-155 showed lower

Statistically significant decrease in pain up to 6 h after dosing In Phase II trials for chronic pain [210] Statistically significant improvement in pain symptoms within 30 min of administration and sustained improvement in pain symptoms for up to 4 h In Phase II trials for postoperative and cancer breakthrough pain [210] Did not achieve a statistically significant decrease in pain intensity [211] ClinicalTrials.gov Identifier: NCT01096966. Phase III trial initiated by Impax is expected in late 2014 [212] No results available for Phase III study

May be effective in patients with CLBP who experience opioid-related adverse effects. ClinicalTrials.gov Identifier: NCT01633944 NCT01675167

Comment

CLBP: Chronic low back pain; ER: Extended release; HAL: Human abuse liability; IR: Immediate release; N/A: Not available; NDA: New Drug Application; NRS: Numeric rating score; OA: Osteoarthritis; ORL: Opioid receptor ligand; OXN: Oxycodone/naloxone controlled release; RCT: Randomized controlled trial; wk: Weeks.

Acetaminophe- Mallinckrodt n+hydrocodone, MNK-155 (COV-155) ER oral formulation of hydrocodone

Phase II; n = 263


DUR-843

Durect

Phase Ib; n = 24

Phase Ib; n = 21

Phase III; n = 462

Phase III; n = 511

Stage of development

Dex-IN, Dexmedotomidine (sublingual)


Dex-SL, Dexme- Orion Pharma dotomidine (sublingual)

Pain mechanism Nociceptive pain, neuropathic pain

Company

Buprenorphine, BioDelivery BEMA LA Sciences (EN-3409)

Compound

Table 1. New formulations of existing compounds.



5

6

Company

Pain mechanism


RCT; n = 24

Phase III; n = 600

RCT; n = 44

Phase III n = 389


Oral


Opioid µ-receptor Oral agonist competitive antagonist at µ, d and k-opioid receptors

Opioid µ-receptor agonist

Mechanism of action

Follow-up period

Single-center, randomized, double-blind, placebo- and activecontrolled study in

Randomized, doubleblind, placebo-controlled study in opioid-exposed subjects with moderateto-severe CLBP

N/A

12 wk

Mechanical manipulation N/A and pharmacokinetic studies in healthy male and female volunteers

double-dummy, activeand placebo-controlled seven-way crossover HAL study assessing the abuse potential of orallyadministered MNK-155 in healthy male and female nondependent recreational opioid users Multicenter, randomized, 12 wk double-blind, placebocontrolled in opioid-naı¨ve and -experienced patients with CLBP

Study design

Sustained release, abusedeterrent oral formulation of oxycodone showed a significant reduction in pain compared with placebo [214]; It may be useful in high-risk patients on opioids. ClinicalTrials.gov Identifier: NCT01685684 DETERx beads retained their ER properties after mechanical tampering and chewing by study subjects [215] Three additional compounds utilizing the DETERx bead technology in preclinical stages of development (COL-172, COL-195, COL-196) [216] Significant decreased in pain scores at wk 12. May be useful in high-risk patients on opioids. ClinicalTrials.gov Identifier: NCT01358526 Significant reductions in drug-liking following administration of OXN compared with oxycodone;

subjective abuse-related effects than an IR hydrocodone bitartrate/ acetaminophen formulation [213]

Comment


Targiniq ER, Purdue Pharma Nociceptive OXN, LP pain, neurooxycodone + pathic pain naloxone ER formulation of oxycodone and naloxone in a fixed 2:1 ratio

Oxycodone Collegium Nociceptive DETERx, Pharmaceutical pain, neuroCOL-003 pathic pain Tamper-resistant, sustainedrelease oral formulation of oxycodone

and acetaminophen

Compound

Table 1. New formulations of existing compounds (continued).


E. Hsu et al.


Allodynic Therapeutics

Alpharma, Pfizer

Company



Pain mechanism

Phase II; n = 78

RCT, n = 41; RCT, n = 32

Phase III; n = 281



Opioid µ-receptor Oral agonist Opioid k-receptor agonist a 2 adrenoreceptor agonist competitive antagonist at µ, d and k- opioid receptors

Opioid µ-receptor Oral agonist competitive antagonist at µ, d and k- opioid receptors

Mechanism of action

Follow-up period

Two abuse potential N/A studies randomized, double-blind, double-dummy, placeboand active-controlled, 6-way crossover study in healthy, nondependent, recreational opioid users with oral administration; randomized, double-blind, placebo- and activecontrolled, 4-way crossover study in healthy, nondependent, recreational opioid with intranasal administration Randomized, double3 wk blind, placebo-controlled trial in subjects with chronic spinal pain in the lumbar, thoracic or cervical regions

Multicenter, randomized, 12 wk double-blind, placebocontrolled study of subjects with moderateto-severe CLBP

nondependent recreational opioid users

Study design

Completed Phase II for CLBP. Results not available. ClinicalTrials.gov Identifier: NCT01415895 Phase III trials for trigeminal neuralgia were withdrawn prior to enrollment for undisclosed reason. ClinicalTrials.gov Identifier: NCT01920087

comparable to placebo [217] Available in 29 countries outside US [218] 57.5% had at least 30% decrease in NRS of pain compared to 44% patients treated with placebo; it may be useful in high-risk patients on opioids. 39.7% patients had at least a 50% decrease in NRS of pain compared to 29.9% patients in the placebo group Statistically significant lower scores for drug-liking and ‘high’ than equivalent doses of crushed IR oxycodone. Statistically significant lower scores for drug-liking and ‘high’ relative to crushed IR oxycodone [219]

Comment


Naltrexone + clonidine, ATNC-05

Oxycodone + naltrexone, ALO-02

Compound




7

8

Company


Nociceptive pain


Pain mechanism

Phase II; n = 127

Phase II


NSAIDs

Opioid µ-receptor agonist, opioid d-receptor agonist, opioid k-receptor agonist

Mechanism of action

Transdermal

Oral


Comment

May have few side effects. No results published . ClinicalTrials.gov Identifier: NCT00759330. Drug does not appear on webpage of company pipeline, another compound TPH-023 appears, but no other information of registered trials is available [221]

No information Ongoing Phase II trials for available chronic pain [220] may be useful in high-risk patients on opioids

Follow-up period

Multicenter, randomized, 1 wk double-blind, placebocontrolled study in patients with CLBP

No information available

Study design


Morphine+oxyc- QRxPharma odone, Q-8011CR (MoxDuoCR) abuse-deterrent formulation of oral controlled release combination of the opioids morphine and oxycodone Flurbiprofen Teikoku Tape

Compound



E. Hsu et al.


N/A

Pregnenolone




Pain mechanism


Oral

Intravenous

Serotonin and Oral norepinephrine reuptake inhibitor

Mechanism of action

Bisphosphonate; mechanism of analgesic effect possibly related to inhibition of Phase II; osteoclasts and painn = 44 inducing substances (IL-1, PGE-2, lactic acid, etc.) Phase II and III; GABAa receptor n = 90 modulation, antiinflammatory effects

Phase II; n = 0/48

Phase II; n = 35

Phase IV; n = 18


CLBP: Chronic low back pain; LBP: Low back pain; mo: months; PGE: Prostaglandin E; VAS: Visual Analog Scale; wk: Weeks.

N/A

Forest/Cypress

Milnicipran (Savella)

Pamidronate

Company

Compound

Table 2. New indications for existing compounds.

Randomized, doubleblind, placebo-controlled in patients with radicular pain related to lumbosacral disc disease Randomized, doubleblind, placebo-controlled study in 35 patients with chronic neuropathic LBP Randomized, doubleblind, placebo-controlled in patients with degenerative disk disease Randomized, double blind, placebo-controlled in patients with nonspecific, mechanical predominantly axial CLBP Randomized, double blind, placebo-controlled in patients with CLBP

Study design

6 wk

Currently recruiting; ClinicalTrials.gov Identifier: NCT01898013

Significant reduction in pain reported compared to placebo [67]

6 mo

6 mo

6 wk

Reduction in pain scores observed but no statistical analysis provided. ClinicalTrials.gov Identifier: NCT01777581 Effect size of VAS pain effect was 0.22. ClinicalTrials.gov Identifier: NCT01225068 Currently recruiting; ClinicalTrials.gov Identifier: NCT01799616

Comment

10 wk

Follow-up period



9

10


Pfizer, Lilly

Tanezumab (RN624)

TNF a inhibitor

Phase II -- III; n = 84

Nociceptive pain Phase II; n = 389

Phase II; n = 1347

Epidural

Oral

NGF antagonist Subcutaneous

NGF antagonist Intravenous or subcutaneous

ORL-1 receptor agonist

Mechanism of Route of action administration

Phase II; n = 1089


Nociceptive pain Phase II; n = 225

Nociceptive pain, neuropathic Pain Nociceptive pain, neuropathic pain

Indication

Follow-up period

Multicenter, randomized, double-blind, placebocontrolled study in patients with moderateto-severe CLBP.

Multicenter, randomized, double-blind, placeboand active-controlled study in patients with CLBP

12 wk

16 wk

Randomized, double14 wk blind, placebo-controlled study in patients with moderate-to-severe CLBP Multicenter, randomized, 6 mo double-blind, placebocontrolled study in patients with lumbosacral radiculopathy comparing etanercept to steroid and saline Multicenter, randomized, 12 wk double-blind, placeboand active-controlled study in patients with CLBP requiring regular use of analgesic medication

Study design

CLBP: Chronic low back pain; d: Days; LBP: Low back pain; mo: Months; NGF: Nerve growth factor; OA: Osteoarthritis; ORL: Opioid receptor ligand; wk: Weeks.

Amgen

Amgen, Pfizer

Etanercept

Fulranumab (AMG-403, JNJ-42160443)

Grunthal

Company

Cebranopadol (GRT 6005)

Compound

Table 3. Novel mechanisms of action.


Greater proportions of patients reported ‡ 30 and ‡ 50% reduction in acute LBP with tanezumab versus naproxen (p £ 0.013) and placebo (p < 0.001) [79] ClinicalTrials.gov Identifier: NCT00584870 Tanezumab 10 and 20 mg had similar efficacy profiles and significantly improved pain scores versus both placebo and naproxen [80]. ClinicalTrials.gov Identifier: NCT00876187. Clinical trials suspended at request of FDA over concerns of rapidly progressive OA leading to joint replacement [81]. Pfizer received notification from the FDA on 19 July 2013 that the clinical hold for tanezumab had been lifted pending the submission and review of nonclinical data [82] Phase II trial terminated due to lack of efficacy; ClinicalTrials.gov Identifier: NCT00973024

Modest improvement in leg and back pain, but worse disability index related to sleep and sex [94]. ClinicalTrials.gov Identifier: NCT00733096

Study completed. Not published. ClinicalTrials.gov Identifier: NCT01725087

Comment

E. Hsu et al.

Mesoblast, Ltd

Red de Terapia Nociceptive Celular (Vallapain, neurodolid University) pathic pain

Mesenchymal stem cell



Phase I; n = 0/24

Phase I; n = 0/100

Phase II; n = 141

Phase II; n = 165

Phase III; n = 325

Phase II; n = 39

Stage of development Oral



N-type calcium channel inhibitor

Glial cell modulator

Intradiscal

Intradiscal

Oral

Intravenous

Triple reuptake Oral inhibitor of dopamine, norepinephrine, serotonin, low NMDA receptor affinity

NMDA partial agonist

Mechanism of Route of action administration

Follow-up period

Multicenter, randomized, double-blind, placebocontrolled study in patients with lumbar radiculopathy Randomized, doubleblind, placebo-controlled study in patients with lumbosacral radiculopathy Multicenter, randomized, double-blind, placebocontrolled study in patients with chronic discogenic lumbar back pain Randomized, doubleblind, placebo-controlled study in patients with degenerative disc disease

12 mo

36 mo

6 wk

10 d

Randomized, double12 wk blind, placebo-controlled study in patients with neuropathic CLBP Three multicenter, 3 mo randomized, double-blind, placebo-controlled trials in patients with CLBP

Study design

CLBP: Chronic low back pain; d: Days; LBP: Low back pain; mo: Months; NGF: Nerve growth factor; OA: Osteoarthritis; ORL: Opioid receptor ligand; wk: Weeks.


Neuropathic pain

Zalicus

Neuropathic pain

Neuropathic pain

Z-160

DOV pharmaceutical

Bicifadine

Neuropathic pain

biogen idec

Sponsored by Northwestern University

D-cycloserine

Indication

Neublastin (BG00010)

Company

Compound

Table 3. Novel mechanisms of action (continued).


Not yet recruiting; ClinicalTrials.gov Identifier: NCT01860417

Not yet recruiting; ClinicalTrials.gov Identifier: NCT01290367

Completed, results unpublished. ClinicalTrials.gov Identifier: NCT01655849

ClinicalTrials.gov Identifier: NCT00295711; NCT00295724; NCT00281645; Phase III completed in 2011 but found no significant reduction in pain intensity; results confounded by poor compliance [101] Currently recruiting for Phase II trial. ClinicalTrials.gov Identifier: NCT01873404

Study is ongoing; ClinicalTrials.gov Identifier: NCT00125528

Comment


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REMS for extended release (ER) and long-acting opioid medications [56]. Two abuse-deterrent formulations of opioids have gained recent approval, morphine/naltrexone combination (Embeda; King Pharma) and oxycodone/niacin (Oxecta/Acurox; King Pharma/Acura Pharmaceuticals), with an additional four compounds currently in Phase II or Phase III development. Similar measures have been undertaken with NSAID-class compounds to minimize the risk of serious gastrointestinal (GI) ulceration and hemorrhage by combining an NSAID with a GI protectant. Cost analyses have determined that in certain populations (e.g., the elderly and those on anticoagulants), the cost of treating GI-related adverse events approaches or exceeds the cost of therapy [57-61]. Systematic reviews have determined that combination therapy (i.e., NSAID plus protein pump inhibitor, H2 blocker or misoprostol) may be a more cost-effective strategy than the use of a COX-2 inhibitor [62]. Two compounds have gained recent approval: naproxen/esomeprazole (Vimovo; Pozen/ AstraZeneca) and ibuprofen/famotidine (Duexis/HZT-501; Horizon Pharma). In clinical trials, both formulations significantly reduced the incidence of NSAID-related GI ulcers [52]. New indications for existing compounds The recent success of the antidepressant duloxetine/Cymbalta (Eli-Lilly) in the treatment of neuropathic and nociceptive pain (including LBP) spurred the development of the antidepressant Milnacipran/Savella (Forest/Cypress). Savella is a selective serotonin and norepinephrine reuptake inhibitor currently approved for the treatment of fibromyalgia. Additional compounds with new indications on the horizon include pamidronate, a bisphosphonate whose class has been shown in clinical studies to alleviate pain from osteoporosis, bone metastases and complex regional pain syndrome, suggesting that it may be effective for both neuropathic and nociceptive CLBP [63,64], and the neurosteroid pregnenolone, which has been shown in animal models to alleviate neuropathic and nociceptive pain [65,66]. Pamidronate recently completed a small (n = 44) Phase II trial for nociceptive CLBP in which two infusions were found to provide significant pain relief compared to placebo through 6-month follow up [67]. Another small prospective study in elderly postmenopausal women with osteoporosis and CLBP found that risedronate therapy over 4 months improved LBP in the absence of vertebral fractures, suggesting that bone resorption due to osteoporosis may be a cause of LBP. This is bolstered by the apparent efficacy of bisphosphonates in relieving pain due to bony metastases [68]. A recent meta-analysis of RCTs in patients with bone pain due to metastatic disease showed that the likelihood of experiencing bone pain was significantly lower in patients taking zoledronate compared with placebo [69]. 7.2

Novel mechanisms of action Despite the plethora of potential drug targets represented by the inflammatory milieu underlying CLBP, the actual number of compounds in development is small. In contrast, there are at 7.3

12

least 25 compounds in development for neuropathic pain [70]. Of these 25 compounds, only cebranopadol (Grunenthal), an opioid-like receptor -1 (ORL-1) receptor agonist, is being studied in trials as a possible treatment for CLBP. A similar scenario exists when considering OA-associated pain, whereby nine compounds are currently in development [71]. To place this in context, facet joint (e.g., arthritis) pain comprises ~ 10 -- 15% of CLBP, with the prevalence increasing with age [72]. There are a total of nine compounds currently being developed for CLBP including five anti-nerve growth factor (NGF) antibodies, namely, Tanezumab/RN624 (Pfizer, Eli-Lilly), Fulranumab/AMG-403/JHJ-42160443 (Amgen, Johnson & Johnson), REGN-475 (Sanofi-Aventis/Regeneron), MEDI-578 (AstraZeneca) and PG110 (Abbott).

NGF inhibitors NGF plays a role in the development and maintenance of nociceptive and neuropathic pain. Rodent models of NGF injected locally and systemically in animal models have demonstrated hyperalgesia and allodynia, and inflamed peripheral tissues exhibit elevated concentrations of NGF [73-75]. Furthermore, NGF inhibition and knockout models reveal reduced pain perception in models of acute local inflammation, chronic inflammatory arthritis, OA, postoperative, visceral and neuropathic pain [76]. In RCTs, NGF inhibitors have been effective in different pain conditions including OA, interstitial cystitis and diabetic neuropathy. Four RCTs of three different compounds have been conducted in patients with CLBP, two with tanezumab, one with fulranumab and one with REGN-475. Thus far, only the two trials of tanezumab have been published in peer-reviewed journals, with both demonstrating statistically significant reduction in pain over placebo [77]. Despite demonstrating efficacy in both pain and functional measures for hip and knee arthritis, a Phase II trial evaluating fulranumab as an adjunctive treatment in 389 patients with CLBP inadequately controlled with conventional medications did not demonstrate a statistically significant difference over placebo at week 12 of treatment [78]. Both tanezumab trials studied patients with non-neuropathic CLBP and found superior pain relief and functional improvement over naproxen and placebo at 12 and 16 weeks of follow up, respectively [79,80]. In 2010, all clinical trials for anti-NGF compounds were suspended at the request of the FDA over concerns of rapidly progressive OA and reports of osteonecrosis leading to joint replacement [81]. A 2012 Arthritis Advisory Committee voted unanimously to restart clinical trials scheduled to resume in 2015 due to a lack of evidence for a direct molecular mechanism linking anti-NGF antibodies to joint destruction [82]. Moreover, it was reported that Pfizer received notification from the FDA on 19 July 2013 that the ‘clinical hold’ for tanezumab had been lifted pending the submission and review of nonclinical data [83]. 7.3.1




7.3.2

Glial cell modulators

Following nerve injury, glial cells proliferate at the dorsal root ganglia (DRG) and spinal cord levels where they stimulate the complement component of the immune system, resulting in the release of cytokines, chemokines and cytotoxic substances such as nitric oxide and free radicals, all of which are integrally involved in the development and maintenance of neuropathic pain [6,84]. Much attention has been focused on glial cell inhibitors due to their potential in reducing abuse-related reward and potentiating the analgesic effects of opioids [85]. Although promising in preclinical animal models, glial cell modulators such as pentoxifylline, propentofylline, ibudilast have not demonstrated significant efficacy in clinical trials for neuropathic pain conditions other than CLBP [6,86]. Adverse reactions of FDA-approved glial cell modulators include nausea, vomiting, anaphylaxis and hemorrhage in combination with anticoagulants including NSAIDs. Cytokine inhibitors Cytokine inhibitors have been extensively studied in neuropathic LBP. TNF-a) is the prototypical proinflammatory cytokine due to its prominent role in initiating the activation cascade of other cytokines and growth factors in the inflammatory response. As a drug class, the TNF-a inhibitors are associated with multiple potential adverse events, which include injection-site reactions, infusion reactions, neutropenia, infections, demyelinating disease, heart failure and cutaneous reactions such as psoriasis, malignancy and autoimmune reactions. In preclinical studies, the preemptive administration of TNF inhibitors has been shown to prevent the pathological and behavioral changes associated with application of nucleus pulposus to spinal nerve roots, suggesting a possible role in radiculopathy [87,88]. TNF inhibitors have also been shown in clinical trials to be effective for inflammatory arthritis, including ankylosing spondylitis, indicating that they may be beneficial for mechanical spinal disorders [89]. However, the results of clinical trials in mechanical spinal pain have been mixed. After positive findings from a case series involving 10 patients with acute sciatica, a randomized controlled study by Korhonen et al. found no benefit from a single infusion of the TNF inhibitor infliximab in 40 patients with unilateral sciatica < 12 weeks in duration [90,91]. In another placebo-controlled trial, Genevay et al. demonstrated a modest benefit for adalimumab 6 month after two subcutaneous injections in 61 patients with acute radiculopathy [92]. The results from injections of TNF inhibitors have yielded similar conflicting results. A small, double-blind study comparing perispinal, intramuscular etanercept with placebo found no benefit in 15 patients with acute radicular pain [93]. Two placebo-controlled studies evaluating epidural etanercept failed to show any benefit in patients with neuropathic spinal pain, whereas two other randomized studies demonstrated significant benefit over epidural dexamethasone at 4 weeks and epidural saline through 6 months [94-97]. 7.3.3

Collectively, these findings suggest the possibility of a modest effect for TNF inhibitors in individuals with acute or subacute radicular LBP. Serotonin, norepinephrine and/or dopamine reuptake inhibitors

7.3.4

Inhibition of the reuptake of neurotransmitters involved in pain modulation is the rationale for prescribing antidepressants to treat CLBP. The descending fibers of the dorsolateral funiculus in the spinal cord are responsible for suppressing nociceptive neurotransmission. These fibers contain serotonergic projections from the raphe nuclei, dopaminergic projections from the ventral tegmental area and noradrenergic projections from the locus coeruleus [98]. Several subclasses of antidepressants have being used for treating chronic pain including tetracyclic antidepressants (amoxapine, maprotiline), serotonin and noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran), atypical antidepressants (bupropion, trazodone, mirtazapine, nefazodone), selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine and paroxetine), serotonin, dopamine and noradrenaline reuptake inhibitors (SNDRIs; bicifadine) and TCAs (amitriptyline, doxepin, imipramine, desipramine and nortriptyline) [99]. This class of medications, particularly TCAs, may be associated with anticholinergic side effects (dry mouth, double vision), drowsiness, insomnia/delirium, orthostatic hypotension, QTc prolongation, GI toxicity, weight gain and sexual dysfunction. Bicifadine, a SNDRI with low NMDA receptor affinity that has shown preclinical [100] and clinical efficacy in postoperative pain [101,102], failed to show an effect in patients with CLBP in a Phase III clinical trial. However, a subsequent analysis stratifying patients according to compliance found significant reduction in pain scores compared to placebo in those with higher plasma levels [103]. Based on the APS guidelines for the treatment of CLBP, paroxetine and trazodone were not effective compared to placebo, TCAs were slightly to moderately more effective than placebo, and there was insufficient evidence to judge the effectiveness of TCAs versus SSRIs [29]. Investigational compounds on the horizon include TD-9855, Theravance, a SNRI, in Phase II development in patients with fibromyalgia [104]. Toll-like receptor antagonists Toll-like receptors (TLR) are transmembrane patternrecognition receptors found both intracellularly and extracellularly. Activation of these receptors causes a conformational change and the production and release of proinflammatory cytokines such as IL-6, IL-1b and TNF-a, which are implicated in initiating and maintaining chronic pain states. Additionally, endogenous ligands, damage-associated molecular patterns or ‘alarmins’, released from damaged tissue are hypothesized to be associated with activation of TLR in neuropathic pain. Most research has focused on TLRs role in neuropathic pain, particularly TLR2, 3 and 4, but more recent studies also demonstrate a role in nociceptive pain [105,106]. 7.3.5


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Currently, AV411 (Ibudilast), a TLR4 antagonist which also acts as a glial cell inhibitor, is in clinical trials for chronic migraine and various withdrawal syndromes including from opioids, alcohol and methamphetamines [107]. In clinical trials, the most frequently reported adverse effects were GI in nature including nausea, diarrhea and dyspepsia. Although there is no evidence of efficacy yet for analgesia in clinical trials, this category of drugs has tremendous promise given its safety profile and theoretical role in reducing substance dependence. Novel opioid agonists Opioid drugs are defined by their target receptor types and act both peripherally and centrally to decrease nociceptive pain. They are also used in neuropathic pain but have reduced efficacy in this context and are associated with a wide range of side effects including constipation, nausea and emesis, sedation, respiratory depression, tolerance, dependence and addiction. There are several different endogenous opioid receptors and subtypes including, µ, k, d and ORL-1 which are targets for emerging pharmacotherapy. Receptors are found in both the peripheral system and CNS, with variable distribution. ORL-1 receptors are not expressed in the same areas as µ-, k- and d-opioid receptors. Instead, they are located in the amygdala septum, hypothalamus, thalamus and perikarya in the DRG and spinal cord [108]. Currently, clinically available opioids all act on µ-receptors; there are several opioids in clinical trials that act on other opioid receptors. The potential benefits of opioids such as k-opioid receptor agonists are less sedation, less constipation, less respiratory depression and less addiction [109]. Emerging therapies in this class of drugs include NKTR 181, a µ-opioid in Phase II trials for knee pain for OA. Buprenorphine, which is a partial µ-agonist/antagonist and k-antagonist, is in Phase III trials for efficacy in opioid-tolerant patients with CLBP. Previous RCTs have demonstrated improvement in pain and quality of life with buprenorphine in opioid-naı¨ve patients with CLBP [110,111]. Two Phase II trials have been completed evaluating CR845, an intravenous k-opioid agonist, for postoperative pain after hysterectomy and bunionectomy. Six Phase II studies have been completed evaluating cebranopadol (GRT 6005), an ORL-1 receptor agonist, in patients with pain symptoms ranging from CLBP, knee OA, diabetic neuropathy and bunionectomy pain. In recruitment is a Phase III trial comparing cebranopadol with morphine-prolonged release in patients with chronic cancer pain [70].


7.3.6

a-2 agonists Direct a-2 adrenergic agonists such as clonidine and dexmedetomidine bind to a-2 adrenergic receptors found in central (supraspinal and spinal) and peripheral (smooth muscle) sites. Their clinical utility lies in their ability to provide analgesia, sedation and sympatholysis. There are three different receptor subtypes -- a2A, a2B, and a2C, whose effects are mediated through G-protein receptor coupling to effectors with different mechanisms. Analgesia is mediated through all three 7.3.7

14

receptor subtypes and may result in the alleviation of neuropathic pain [112]. AGN 2038181 (Rezatomidine) is an a2B adrenoreceptor agonist in Phase II clinical trials for diabetic peripheral neuropathy [104]. Although these drugs are widely used in regional anesthesia, their side effects, including bradycardia, hypotension and sedation, will likely limit their use in the chronic setting. Ion channel antagonists Ion channels are ubiquitous components of the plasma membrane of almost all cells in the human body and are characterized by selective permeability to specific electrically charged ions whose entry or exit modulates neurotransmission. Passage through ion channels is governed by a ‘gate’, which may be opened or closed in response to temperature (i.e., transient receptor potential vanilloid type 1 [TRPV1]), ligand binding (i.e., NMDA receptor) or chemical or electrical signals (i.e., voltage-gated sodium channels). 7.3.8

Vanilloid receptor TRPV1 modulators The vanilloid receptor or TRPV1 receptor is a nonselective cation channel expressed both centrally and peripherally [113-117]. It is abundantly expressed on C-fibers and A-delta fibers and localized to DRG and trigeminal ganglia cells [113,114]. Intrinsically, TRPV1 responds to a variety of endogenous ligands as well as changes in pH (< 6), temperature (> 42 C) and membrane depolarization, and receptor activation ultimately leads to the influx of Na+ and Ca2+ ions into cells [116-118]. TRPV1 is upregulated during inflammation and plays a role in inflammation-induced pain behaviors [119-124]. TRPV1 knockout mice exhibit decreased thermal hypersensitivity after inflammation [125,126]. Interestingly, both agonists and antagonists have the ability to provide analgesia, with the TRPV1 antagonist class offering a novel mechanistic treatment for both nociceptive and neuropathic pain. Agonists such as capsaicin (active ingredient in hot chili peppers) and the vanilloid analog resiniferatoxin cause desensitization of TRPV1 channels and relief of pain behaviors in inflammatory, neuropathic and cancer pain models [114,127]. However, human studies have found systemic administration problematic due to the prevalence of side effects (e.g., high blood pressure, respiratory effects). Efforts to create a nonpungent and lower potency agonist (olvanil) did not progress to clinical trials due to poor pharmacokinetics and limited bioavailability [128]. High-dose topical therapy and local injections have shown positive pain relief in some human trials [129]. 4975 (Adlea) developed by Anesiva demonstrated significant reductions in post-bunionectomy, intermetatarsal neuroma, and lateral epicondylitis with a single local injection [130-132]. Two clinical trials evaluating intra-articular injections in patients with end-stage knee OA have been conducted with conflicting results [133,134]. Another compound, Civamide (Zucapsaicin), is an intranasal formulation under investigation for the treatment of cluster and migraine headaches, with mixed results thus far [128]. 7.3.8.1




The potential to treat a broad range of acute and chronic pain conditions has set the stage for an aggressive search for clinically effective compounds [128,135-143]. Current Phase II compounds include DWP-05195 (Daewoong Pharm), AZD-1386 (AstraZeneca), GRC-6211 (Glenmark/Lilly), JTS-653 (Japan Tobacco), MK-2295 (Merck/Neurogen) and SB-705498 (GlaxoSmithKline). Hyperthermia is a potential side effect of TRPV1 agents, and previous trials were either terminated for hyperthermia (AMG 517) [126] or exhibited a significant hyperthermic effect (ABT 102) [124,127,128,144]. Additional Phase II studies evaluating GRC-6211 and AZD-1386 were suspended for undisclosed reasons and elevated liver enzymes, respectively [145]. The emergence of these adverse effects has generated some concern regarding the complexity of TRPV1 and its role in temperature homeostasis [142]. Recently, Trevisani and Gatti described five compounds tested in preclinical animal models that achieved anti-nociception without affecting core body temperature -- BCTP, GRC6211, PHE377, AS1928370 and AS1928370 [143,145-148]. Glutamate receptor subtype NMDA Glutamate is a neurotransmitter with a well-established role in somatosensory pain processing [149]. A noxious peripheral stimuli triggers primary afferent nociceptive terminals to release glutamate which binds to two receptor subtypes: i) kainite; and ii) (R,S)-a- AMPA receptors. With continued activation of nociceptive signaling pathways as occurs in chronic pain, the release of glutamate leads to prolonged membrane depolarization and removal of the tonic magnesium inhibition of the third glutamate receptor subtype, the NMDA receptor [150-153]. Unlike AMPA and kainate receptors, the ability of NMDA receptors to initiate Ca2+-mediated intracellular signaling pathways results in long-term potentiation, opioid tolerance and the development of chronic neuropathic pain [153]. The NMDA receptor ion channel is a complex pharmacological target with a heterotetrameric structure that consists of up to seven subunits, each of which contains numerous allosteric sites which serve as potential targets [154]. The NMDA receptor is widely distributed throughout the CNS and is involved in multiple important physiological (learning and memory) and pathological processes (chronic pain, neurodegeneration and dementia), complicating the development of useful pharmacological agents [153]. Whereas the most obvious target is the ligand binding site, and highly selective and potent NMDA antagonists are available, this class has not shown much utility due to excessive side effects including dissociative anesthesia (amnesia, catalepsy), hallucinations, confusion, agitation and psychosis [153,155]. Attempts to decrease off-target effects have centered on identification of low-affinity channel blockers which can inhibit ‘wind-up’ without affecting physiologically appropriate responses to noxious stimuli [153,156]. However, clinical results have been inconsistent. High-dose dextromethorphan achieved a modest (24%) reduction in pain intensity in 7.3.8.2

patients with diabetic neuropathy but failed to exhibit a significant effect in postherpetic neuralgia patients [157,158]. A double-blind, placebo-controlled trial assessing the antiparkinsonian drug amantadine demonstrated relief of postsurgical neuropathic pain in cancer patients; however, its structurally related analog memantine yielded no difference compared to placebo in patients with diabetic neuropathy, postherpetic neuralgia and phantom limb pain [159,160]. A major challenge in analgesic clinical trials involves inadequate dosing in the face of a narrow therapeutic ratio, and the class of NMDA receptor antagonists is a good example of this -- hence the better responses shown with higher doses of low-affinity NMDA antagonists. Studies by Sang et al. and Nelson et al. showed an effect for high-dose dextromethorphan compared to an inert as well as an active placebo (lorazepam) [160,161]. A 2012 review of novel NMDA receptor modulators by Santangelo et al. discussed two novel agents: i) a PCP analog, bicyclo-4-F-PCP, which demonstrated decreased acute cell line toxicity; and ii) AQ444 compound 8, for use in the treatment or prevention of diseases characterized by impairment of higher cerebral functions [158]. In an effort to develop more selective compounds with potentially reduced side-effect profiles, research has focused on targets such as the NR2B subunit, which is expressed in DRG cells and superficial layers of the dorsal spinal horn -- critical areas of pain processing [162]. Two early drugs ifenprodil and eliprodil failed in development due to crossreactivity with other molecular targets (serotonin receptors, a1-adrenergic receptors and cardiac ion channels) [163]. The development of more selective compounds has met greater success in animal pain models of inflammatory and neuropathic pain, with decreased cross-reactivity profiles [163,164]. One compound, traxoprodil (CP-101,606), provided relief in a clinical trial to patients suffering from both central (spinal cord injury) and peripheral (monoradiculopathy) neuropathic pain, without significant psychomimetic symptoms [165]. The most serious adverse effects were centrally mediated (depression, dizziness, hypoesthesia). Glycine is an obligatory NMDA receptor co-agonist, binding to a site on the NR1 subunit [154]. The binding of glycine potentiates NMDA receptor activity; thus, glycine B antagonists enhance desensitization and reduce NMDA responsiveness. Additionally, glycine B antagonists appear to be devoid of the typical psychomimetic and neurotoxic effects associated with NMDA receptor antagonists. However, these compounds can cause ataxia and motor relaxation [166]. Several glycine antagonists have shown positive effects in preclinical neuropathic and inflammatory pain models [167]. Only one clinical trial has been reported in which the oral administration of GV196771 reduced areas of allodynia but did not improve evoked pain intensity or provide pain relief [167]. Voltage-gated sodium channels Within the human CNS, sodium channels play a role in the generation of nerve impulses in excitable cells such as neurons, 7.3.8.3


15


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glial cells and cardiac myocytes. Existing sodium channel blocking drugs such as lidocaine, mexiletine and tocainide are effective for neuropathic pain, but they are nonspecific and therefore characterized by myriad side effects. Pain research over the past two decades has been focused on identifying sodium channels that are upregulated and heterotopically expressed in DRG and injured axons following nerve injury. There are currently nine different genes that encode nine distinct sodium channel isoforms (NaV1.1 -- NaV1.9), with different amino acid sequences, different physiological properties and different distributions within the nervous system. Of these, five isoforms, NaV1.3, 1.6, 1.7, 1.8 and 1.9 have emerged as attractive molecular targets for pain therapies. NaV1.7 has attracted special interest because of its key role in producing human pain syndromes such as erythromelalgia, an inherited disorder characterized by severe burning pain of the hands and feet caused by a gain-of-function mutation in NaV 1.7, and congenital insensitivity to pain, a disorder in which individuals with a loss-of-function mutation in NaV 1.7 cannot feel painful stimuli. Some NaV1.7 mutations can alter the sensitivity of sodium channels to antagonists such as mexiletine and carbamazepine [168,169]. Several clinically available nonselective sodium channel antagonists belong to the class I antiarrhythmic category and therefore possess negative inotropic and proarrhythmic effects. Other side effects include seizures, dermatitis and hypersensitivity syndromes. In January 2014, the European Commission issued a grant for e4.8 million for the PROPANE study, a multisite, international prospective cohort study that aims to stratify patients with painful neuropathy using targeted genomic sequencing [170]. Although not yet completed, the results could usher in a new era for personalized genomically targeted pain pharmacotherapeutics [171]. Voltage-gated calcium channels Membrane depolarization leads to an opening of voltagesensitive calcium channels, calcium influx into the cell and subsequent neuronal, glial cell and muscle excitation. Preclinical studies have focused on compounds that inhibit N, T and a2d subunit-type calcium channels, thus modulating the release of neurotransmitters at presynaptic terminals in the spinal cord. The most widely used class of agents for CLBP remain gabapentinoids such as gabapentin (including an ER formulation), pregabalin and enacarbil, which act on the a2d subunit. All of these agents were FDA-approved for CNS diseases or neuropathic pain states other than CLBP, and clinical trials evaluating gabapentinoids for CLBP have been decidedly mixed. Although two small randomized trials demonstrated benefit for gabapentin in neuropathic LBP [172,173], a larger randomized controlled study evaluating pregabalin in patients with chronic lumbosacral radiculopathy failed to demonstrate any benefit compared to placebo [16]. For combination therapy, a small randomized trial found the combination of celecoxib and pregabalin to be superior to either drug alone in a mixed CLPB population with 7.3.8.4

16

nociceptive and neuropathic pain, with the most marked benefit noted in those with neuropathic pain [174]. However, a much larger study conducted in patients with neuropathic LBP found no difference between tapentadol prolonged release as a stand-alone therapy and tapentadol prolonged release in combination with gabapentin [175]. A major challenge to the development of drugs within this class is the ubiquitous distribution of calcium channels in neurons, glial cells, pacemaker cells, myocytes and even osteocytes [176]. Current pharmaceutical development has focused on N- and T-type calcium channel blockers which illustrate off-target effects. For example, ziconotide, a selective N-type calcium channel blocker FDA approved in 2004, is restricted to intrathecal delivery, contraindicated in psychosis and associated with a high incidence of side effects, including neurological and psychiatric [177]. Several calcium channel blockers used for other indications have been withdrawn from the market or fallen out of use due to safety concerns such as mibefradil, pimozide and penfluridol. Several agents targeting calcium channel blockers aiming to overcome the limitations in drug delivery and safety are currently in Phase II clinical trials for various neuropathic pain states, including DS-5565 (a2d), CNV-2197944 (N-type) and ABT-639 (T-type). The only calcium channel modulating agent (Z-160) studied in lumbar radiculopathy failed to show efficacy in a Phase II trial [70]. Voltage-gated potassium channels Voltage-gated potassium channels are also involved in the generation of action potential in neurotransmission. Even more so than calcium channel blockers, development of a targeted treatment for pain is challenged by the ubiquity of potassium channels in multiple tissues. Furthermore, potassium channels are encoded by > 70 genes with a high degree of sequence similarity among subclasses of channels [178]. Drug--drug interactions also represent a major challenge to potassium channel analgesics since opioid receptor agonists open potassium channels and NMDA receptor antagonists close potassium channels; this may lead to or potentiate adverse effects such as sedation. Due to these challenges, development of clinically ready potassium channel modulators is still at a preclinical stage and is focused on selection and validation of pain-specific ion channels such as KCNQ, Kv2 and Kv9.1 [178]. 7.3.8.5

Nitrous oxide and PDEs Nitrous oxide released from damaged afferent nerve endings activates soluble guanylyl cyclase, catalyzing the formation of second messenger cGMP, resulting in the sensitization of nearby neurons and hyperalgesia [179]. This effect is terminated by cGMP-specific PDE hydrolysis of cGMP. Several animal studies have demonstrated clinically significant antinociceptive effects with local, systemic and intrathecal administration of PDE5 inhibitors [180,181]. These therapeutic effects have been observed in both nociceptive and neuropathic pain models. Rocha et al. demonstrate dose-dependent 7.3.9




analgesia in rodent OA models treated with tadalafil, suggesting possible benefit for facetogenic CLBP [181]. Huang et al. were able to show analgesic effects for intravenous sildenafil in models of neuropathic pain induced by spinal nerve ligation [182]. Two other studies found a synergistic effect between sildenafil and morphine for both oral and intrathecal administration [180,183]. Human studies demonstrating analgesic effects are lacking. Side effects of this drug class include hypotension, hypertension, angina, priapism and vision loss. To date, only a single Pfizer-sponsored Phase IV clinical trial has been conducted in the treatment of diabetic neuropathy pain in the mid-2000s, with no results reported. Gene therapy An ideal therapeutic would be one that inhibits neurotransmission at a functionally specific site such as peripheral neurons or spinal cord/DRG without off-target side effects. Viral vector-based gene therapy has demonstrated safety in one Phase I clinical trial for cancer pain [184]. Promising data from a Phase I study of a DNA-decoy drug AYX-1 for preventing post-surgical pain following total knee replacement offers the possibility of preventing the transition between acute and chronic post-surgical pain using gene therapy [185]. However, several following factors deserve consideration when designing a suitable therapy: i) therapeutic gene selection; ii) specificity of the viral vector to the appropriate target cells; and iii) vector production quality and cost. The current state of evidence for efficacy of various viral transduction methodologies is limited to animal studies [186]. In the short term, gene therapy requires further validation of efficacy and safety in CLBP. However, the ability to specifically target the mechanism (nociceptive, neuropathic, mixed) and tissue (disc) offers substantial promise. 7.4

Stem cell therapy The promising results of feasibility studies using stem cell therapy in treating neurodegenerative conditions such as amyotrophic lateral sclerosis and multiple sclerosis has spurred interest in using stem cell therapy to treat neuropathic pain [187,188]. The evidence for efficacy of this modality is still preclinical [189], but two human studies using allogeneic mesenchymal stem cell intradiscal transplants were recently submitted to the ClinicalTrials.gov registry [190,191]. We believe there is still significant uncertainty over using stem cell therapy for CLBP including safety and quality concerns such as immunogenicity, bacterial or viral contamination and misdirected or uncontrolled growth. However, over the long term, gene therapy offers unprecedented opportunities to move pain management from symptom mitigation to disease modification. 7.4.1

8.

Potential development issues

There are several challenges related to the development of novel analgesics for CLBP. A substantial number of clinical

trials exist for analgesic drugs that, even though they have previously shown efficacy, have yielded negative results [192-195]. One explanation for this phenomenon is that intrinsic characteristics of clinical trials can compromise their ability to reveal efficacy [196]. In this context, one objective is to increase the ‘ability to distinguish an effective from a less or ineffective treatment’, a concept known as assay sensitivity [197]. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials has developed consensus guidelines to identify factors that influence assay sensitivity with the goal of reducing the rate of false-negative trials [196]. This report identified several areas of patient, study design, study site and outcome measurement factors that could affect the assay sensitivity and efficiency of chronic pain clinical studies such as psychological distress, which was associated with a higher placebo response and less treatment improvement in one clinical trial examining opioids in the treatment of LBP [198]. Another barrier to clinical development is adverse effects. Whereas reports of serious adverse events associated with the use of medications for LBP are sparse [199-201], many analgesic agents are centrally acting and common side effects such as sedation, dizziness and fatigue can lead to a high rate of withdrawal from studies [202,203]. In one study comparing topiramate with diphenhydramine for lumbar radiculopathy, topiramate was associated with more than twice the rate of withdrawal due to adverse events such as sedation and diarrhea [204]. This led the investigators to not recommend using a medication that was more efficacious than an active placebo. The cost of clinical trials in CLBP represents another barrier to the development of novel analgesic medications. In the case of clinical trials for LBP, the cost of conducting expensive trials is compounded by the poor predictive value of preclinical animal models, which increases the false-positive rate of drug candidates advanced to human testing [104,205,206]. Improving the efficiency of studies that advance into latestage testing is, therefore, a worthwhile endeavor [196]. 9.

Conclusions

It is important to note the importance of accounting for effect size and nonspecific effects that may confound study results. It is difficult to compare treatment studies in CLBP due to variability in the type and precision of pain outcome measures. For example, efficacy studies of novel analgesics for CLBP may use different measures of pain severity (Numeric Rating Scale, Visual Analog Scale, percentage decrease from baseline, etc.). Because each measure contains different scales, comparing the magnitude of an effect can be challenging. Computing an effect size is critical to prove that there is a difference between a study drug and comparator. Two well-accepted measures of effect size are commonly used, namely: i) the standardized mean difference, which is used for continuous measures such as a pain intensity rating scale; and ii) the number needed to treat,


17


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which is used for binary outcomes such as responder versus nonresponder [207,208]. Interestingly, regardless of treatment type or measurement, improvement in LBP symptoms follows a distinct pattern. In a recent meta-analysis of both RCT and observational studies of patients with LBP, Artus et al. showed that patients experienced rapid improvement in the short term then smaller improvement in the intermediate and long term [209]. Drug discovery in CLBP must weigh the potential to create substantial value against the risk of causing individual and societal harm. CLBP is particularly challenging given the wide spectrum of different and often overlapping etiologies. Furthermore, the concept of LBP as a biopsychosocial phenomenon warrants repeating. Utilizing this definition helps to explain the limited long-term effects of all single modality treatments and interventions for LBP including pharmacotherapy and underscores the need to develop better physical, psychological and social interventions in addition to novel drug therapy. Challenges to developing better medicines specific to CLBP include: 1) heterogeneity of pain phenotypes within a given pain diagnostic category; 2) biological resiliency of multiple concurrent nociceptive pathways such that unimodal therapy is often inadequate in modulating established chronic pain conditions; 3) inability to identify pathophysiological disease mechanisms specific to an individual patient; 4) lack of consensus over outcome measures; 5) off-target and sometimes dangerous side effects; and 6) inconsistent treatment delivery approaches, which are often empirical rather than mechanism-based. [5]. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Hoy D, Bain C, Williams G, et al. A systematic review of the global prevalence of low back pain. Arthritis Rheum 2012;64:2028-37

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Juniper M, Le T, Mladsi D. The epidemiology, economic burden, and pharmacological treatment of chronic low back pain in France, Germany, Italy, Spain and the UK: a literature-based review. Expert Opin Pharmacother 2009;10:2581-92

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Expert opinion

Despite these challenges, the volume and diversity of novel molecular entities spanning chemical, biological, gene- and cell-based modalities reflect the level of interest and investment in this field. The paradigm of mechanism-based rather than empirical treatment underscores the need for drugs with diverse mechanisms of action. Genotype- or phenotype-specific therapy based on the results of multinational collaborative research such as the PROPANE study offers the prospect of targeted, individualized therapy [170]. Early stage efforts in gene- and stem cell-based therapies may ultimately lead to diseasemodifying therapy for CLBP rather than symptom alleviation alone. In the effort to improve collaboration around pain care, several national and international collaborations are ongoing, spanning topics from clinical trial design, patient-reported outcomes registries and more effective strategies to deliver and reimburse safe pain care [5].Continued collaborative efforts from multidisciplinary centers, and aligning research and clinical care around validated clinically appropriate outcome measures is critical in making progress toward identifying highvalue treatments and treatment plans for patients with CLBP.

Declaration of interest This paper was funded in part by the Centers for Rehabilitation Sciences Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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clinical implications. BMJ 2014;348:f7656 A recent overview explaining the rationale and importance of mechanism-based treatment over disease-based treatment.

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Eugene Hsu1 MD MBA, Sunberri Murphy2 DO, David Chang2 DO & Steven P Cohen†3 MD † Author for correspondence 1 Fellow in Anesthesiology and Perioperative Medicine, Oregon Health and Science University School of Medicine, Portland, OR, USA 2 Resident in Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 Professor of Anesthesiology and Physical Medicine and Rehabilitation, Johns Hopkins School of Medicine and Uniformed Services University of the Health Sciences, 550 North Broadway, Suite 301, Baltimore, MD 21205, USA Tel: +1 410 955 1822; Fax: +1 410 614 7592; E-mail: [email protected]

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Non-steroidal anti-inflammatory drugs for chronic low back pain.

Therapeutic ultrasound for chronic low-back pain.

Corticosteroid injections for chronic low back pain.

Chronic low back pain patient and spouse.

TENS for chronic low back pain.

Health utilities for chronic low back pain.

TENS for chronic low-back pain.

Pain intensity measurement in chronic low back pain.

The effect of chronic low back pain on tactile suppression during back movements.

Effect of Togu-exercise on Lumbar Back Strength of Women with Chronic Low Back Pain.

Chronic Q fever diagnosis— consensus guideline versus expert opinion

Emerging drugs for neuropathic pain.

Core strength training for patients with chronic low back pain.

Predictors of self-management for chronic low back pain.

Accelerometer-Determined Physical Activity and Clinical Low Back Pain Measures in Adolescents With Chronic or Subacute Recurrent Low Back Pain.

Personality traits in patients with acute low-back pain. A comparison with chronic low-back pain patients.

Low-back pain.

Low back pain.

Postpartum low-back pain.

Surface Electromyographic (SEMG) Biofeedback for Chronic Low Back Pain.

Discriminant analysis of neuromuscular variables in chronic low back pain.

Acupressure for chronic low back pain: a single system study.

The relationship between cigarette smoking and chronic low back pain.

Prevalence of chronic low back pain: systematic review.