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New Targets In Pain, Non-Neuronal Cells, And The Role Of Palmitoyletha- Nolamide
Sep 12, 2018

Department of Pharmacology  and Toxicology, University of Witten/Herdecke, Germany 

Abstract: Persistent pain in neuropathic  conditions is often quite refractory to conventional  analgesic therapy, with most patients obtaining, at best, only partial relief of symptoms. The tendency still exists to treat these complex pains with one or a combination  of two analgesics  at the most. Given the complex nature of the underlying  pathogenesis,  this approach more often than not fails to produce  a meaningful  improvement.  New targets are therefore  badly needed. In this regard non-neuronal  cells – glia and mast cells in particular - are emerging as new targets for the treatment of neuropathic  pain. An extensive preclinical database exists showing that the naturally occurring fatty acid amide palmitoylethanolamide is endowed with anti-inflammatory  activity, and clinical trials assessing the efficacy and safety of palmitoylethanolamide in neuropathic pain have been successful in generating proof-of-concept  for treatment in man. Here I will review salient pre- clinical  and clinical  evidence  supporting  non-neuronal  cells as viable targets in the treatment  of neuropathic  pain. This will be followed by a discussion of recent proof-of-concept  clinical trials demonstrating  the efficacy and safety of palmi- toylethanolamide  in the treatment of various neuropathic pain states.

Keywords: New targets, pain, non-neuronal cells, palmitoylethanolamide.

 

EMERGENCE OF A MULTI-MODEL THERAPY FOR PAIN 

The pharmacotherapy  of pain is evolving from a step-by- step approach to a multimodal therapy which, I believe, is destined to become the hallmark in how we treat neuropathic pain in the future. However, the literature at present provides little guidance on a suitable treatment regimen to follow. Current focus remains on the modulation of functions of the nervous system itself, especially ion channels, without taking other players into consideration - glia, mast cells, and other immune-competent cells. This is unfortunate, as the major players in the pathogenesis of chronic neuropathic pain most probably are these non-neuronal cells. 

Generally, there is a hierarchy of treatments for neuro- pathic pain physicians will mostly follow, starting often with monotherapy   and   increasing   to  maximal   tolerated   dose. When high-dose monotherapy proves insufficient or intoler- able side effects prevent optimal pain control, combinations of various pharmacologic  compounds follow next. The latter may comprise combining serotonin-noradrenaline uptake inhibitors, tricyclic antidepressants, anticonvulsants, opioids, natural and synthetic derivatives from Cannabis, endocan- nabinoids and topical analgesics. [7-10]

Most clinical studies have been conducted in painful polyneuropathy associated with diabetes, followed by postherpetic neuralgia. Studies in other types of neuropathic pain, such as pain in chronic idiopathic axonal polyneuropa thy, chemotherapy-induced  pain and central neuropathic pain

as in stroke and multiple sclerosis (MS) are rare; even more rare are studies in spinal pain syndromes.

 

THE STATIC NATURE  OF ANALGESIC THERA- PEUTIC EFFICACY 

Although our understanding of neuropathic pain- generating mechanisms has  advanced  considerably   since

2000, there has not been a corresponding improvement in treatment efficacy. Opiates and drugs such as amitriptyline remain unsurpassed as therapeutics. 

Finnerup et al., evaluated the 69 randomized con- trolled  trials  published  in  the  past  5  years  and compared these to the 105 trials published  in the preceding  39 years. Their conclusion was intriguing: no real improvement in the treatment of neuropathic pain has been achieved, and recent clinical trials of older analgesics  seem even to show an in-crease in numbers needed to treat (NNT)1. 

These  authors  further  analyzed   all  completed   clinical trials to date, to identify negative trials and publication bias. In addition  to the published  trials, their database  presented one  trial  examining  gabapentin  3600  mg,  which  relieved painful polyneuropathy with an NNT of 7.0 (4.3–20), as well as four positive and three negative trials with pregabalin, revealing  a combined  NNT of 9.5 (6.8–16.0).  The observa- tions imply that the figures most often quoted on NNT’s of analgesics are flawed; these analgesics might be even less efficacious than previously thought. This fact, together with

the relative high numbers needed to harm2  makes one work- ing in this field quite humble  

It is clear, especially for scientists working in the field of drug targeting, that most, if not nearly all of the current anal- gesics have one thing in common: targets are most often ion channels or surface receptors of neurons. [13-15] In this re- gard, non-neuronal cells and nuclear receptors such as perox- isome proliferator-activated   receptors  (PPARs)  have emerged as important targets in a variety of pain states. In this short review we will address some aspects in this emerging field related to non-neuronal targets in chronic and neuropathic pain.

 

NON-NEURONAL CELLS  AS  NEW  TARGETS  FOR NEUROPATHIC PAIN

Today, there is good evidence  that the major players  in the pathogenesis  of chronic neuropathic pain most probably are non-neuronal  cells. Mast cells, for example,  have been the recognized  to play a causative role in the develop- ment of hyperalgesia following nerve injury, and their pathogenic   involvement   has   also   been   demonstrated   in chronic low back pain, visceral or pelvic pain, [21-and migraine. Moreover, mast cell degranulation distinctly activates trigemino-cervical and lumbosacral pain pathways and elicits widespread tactile pain hypersensitivity. Together  with  glia,  and  especially  microglia  that  are known to functionally interact with mast cells, these immune cell types are now considered to be key to the phe- nomena of central and peripheral sensitization. .

Garrison  et al.,were  the  first  to  demonstrate  that after a unilateral ligation of nervous ischiadicus, unilaterally spinal glia became activated, swollen  and a new phenotype of  activated  glia  induced. This  observation  was  soon  fol- lowed by comparable findings in a variety of other studies. Peripheral nerve injuries induce a low-grade inflam- mation in the dorsal horns of spinal cord and along the pain pathways  to the thalamus and further to the parietal cortex, due to the activation of Schwann cells, glial cells (espe- cially microglia), and the production of cytokines and other inflammatory  mediators  within  the PNS  and  CNS.Such  neuroinflammatory  activity  leads to the consolidation of the winding up phenomena, the central and peripheral sensitization. [39] Schwann cells, glia, microglia and astro- cytes therefore play a central role in the pathogenesis of neuropathic and chronic pain. Gliopathic pain or asteropathic pain  might  even  become  new  synonyms  for  neuropathic pain. There are data to support chronic pain syndromes such as  rheumatoid  arthritis  and  fibromyalgia  as  also  linked  to glia cell activation.  

Interestingly, also breakthrough pain (i.e., the transient exacerbation of pain experienced by a patient with relatively stable and controlled baseline pain) has been hypothesized to be due, at least in part, to glia hyper-reactivity. 

In a recent hallmark paper by Ohara et al., the term

'gliopathic  pain'  indeed  was  coined.  Glia,  astrocytes  and other immunocompetent cells directly influence neurotrans- mission  between  two  neurons,  and  the recently  introduced terminology ‘pentapartite synapse’ indicates the profound influence of these non-neuronal  cells on neurotransmission. [46, 47] Glia-modulating  drugs will therefore become a new class of analgesics, enhancing our pharmacotherapeutic ar- mamentarium. [3,44, 48, 49] The first prototype is already available for human use. It is the endogenous fatty acid am- ide palmitoylethanolamide  (PEA), and in more than 20 clini- cal trials the efficacy and safety of this compound have been documented  and will be discussed later in this article. Thus, proof-of-principle  (POP) for non-neuronal  cells as targets in neuropathic  pain  has  been  established.  Because  many  of these clinical studies have been published in Italian or Span- ish  journals,  and  the  English  speaking  community  might have missed this important new chapter in the treatment of chronic pain, we now focus on the endogenous non-neuronal cell modulator PEA.

 

PEA  - AN ENDOGENOUS ANALGESIC AND MODU- LATOR OF GLIA  AND MAST CELLS 

PEA is a naturally occurring  fatty acid amide belonging to the class of endocannabinoids  which include, among oth- ers  anandamide,  oleoylethanolamide,   stearoylethanolamide and lauroylethanolamide.

Amide lipids like PEA are widely distributed in nature, in a variety of plant, invertebrate,  and mammalian tissues.

PEA  is  available  in  some  European   countries  (Italy, Spain, the Netherlands, and since 2011 also in Germany) for the treatment of chronic pain and chronic inflammation, as a diet food for medical purposes (Normast TM).

PEA  first  attracted  attention  in 1957,  with  its  isolation from soybeans,  peanuts,  and egg yolk and identification  of anti-inflammatory  activity [53]. PEA is produced on demand and accumulates locally during several inflammatory and painful disorders, e.g. intestinal inflammation, [54] chronic migraine,  [55] neuropathic  pain, [56, 57] cerebral ischemia [58] and MS. [59] Increase in PEA local levels is unques- tionably considered to play protective and pro-homeostatic roles.  [60]  PEA  exerts  anti-inflammatory  and  anti- hyperalgesic  effects in various animal models of inflamma- tion and pain [60, 61] and it has been suggested to function as an endogenous regulator of nociception.

Since the first paper  on PEA was indexed  in Pumed  in 1968  nearly 300 entries have appeared, under the key- word 'palmitoylethanolamide'.  In the 1990s the relationship between  anandamide   and  PEA  was  first  described,  with growing  insight  into  the  function  of  the  endocannabinoids such   as  oleamide,   2-lineoylglycerol,   2-palmitoylglycerol, and investigation into their capacity to modulate pain sensi- tivity and inflammation. In the course of these studies it emerged that PEA could alleviate, in a dose-dependent  man- ner, pain behaviors elicited in mouse pain models and down- regulate mast cell hyperactivity. 

Mast cells are immunocompetent cells often found in proximity to sensory nerve endings. Their degranulation (i.e. the release of dozens of bioactive mediators stored in intra- cellular granules) can enhance the nociceptive signal, which is why peripheral mast cells are considered to be pro- inflammatory  and  pro-nociceptive. For  example,  mast cells synthesize,  store and release nerve growth factor,which itself produces inflammation and sensitization of the peripheral terminals of sensory neurons. Mast cells are found also in the spinal dura, the thalamus and the dura ma- ter. Conceivably, PEA may represent a new thera- peutic approach for migraine,  as meningeal nociceptors  can be activated locally through a neuroimmune interaction with resident  mast cells populating  the dura  mater.Human mast cells release a vast array of mediators, which may well account for the mast cell’s broad involvement in physiologi- cal and pathophysiological  functions and diseases. Mast cell modulation by PEA might thus be relevant for disorders such as bladder pain, pelvic, pain, sciatic pain, headache, postsur- gical pain, prostate pain and male infertility, chronic regional pain syndrome (CRPS), burning mouth syndrome, and mast cell activation syndrome, among others. 

Indeed, there are numerous examples of PEA down- modulation of mast cells in vitro and in vivo, resulting in decreased release of various bioactive mediators (i.e., hista- mine,   tumor   necrosis   factor-alpha,   prostaglandins,   nerve growth factor, serotonin). [81-84] This, in turn, produced clinical effects such as pain relief and better motor function after spinal cord injury. 

Furthermore, PEA protects microglial cells from excito- toxicity, Microglia possess the machinery to synthesize and hydrolyze PEA.PEA is able to control the micro- glial   behaviour and   revert   microglial   hyper- activation in the spinal cord during experimental neuropathic pain, suggesting targeted glial effects of PEA in the CNS of chronic pain-affected subjects. 

 

MAIN TARGET OF PEA:  PPAR-α

PEA mechanism(s) of action is still a matter of debate, although it seems that the antinociceptive  effect is mediated by multiple mechanisms (i.e., multimodal mechanism of action). Membrane  receptors  (i.e.,  cannabinoid  recep- tors),nuclear receptors (i.e. PPAR),neuroster- oid synthesis,mast cell down-modulation and control of microglial activation are all purported mechanisms of action of PEA. These may coexist, depending upon  the physiological  and pathophysiological  circum- stances. 

A separate effect, the so called entourage-effect, has been used to explain PEA biological activities. Although PEA affinity for cannabinoid CB1 and CB2 receptors is very low, its antinocicepive effects are prevented by the can- nabinoid receptor antagonists.Thus when referring to PEA, it is now preferable to use the term “cannabimimetic compound” or “indirect endocannabinoid” . 

Although PEA has affinity for other PPAR isoforms, G- coupled  receptors,  novel  cannabinoid  receptors,  and  recep- tors  GPR55  and  GPR119  with  an  unknown  function, PPAR-α may be the main biological target of PEA.

PEA up-regulates  PPAR-α  in a model of spinal cord in- jury.  In this injury model, PPAR-α is down-regulated, resulting in activation of inflammatory cascades leading to tissue destruction. PPAR-α  activation by PEA inhibits these detrimental  cascades.  Delta9-tetrahydrocannabinol  also  ex- erts neuroprotective properties, most probably via a PPAR-α mechanism of action. PEA up-regulation of PPAR-α results  in decreased  output  of inflammatory  mediators  like


tumor  necrosis  factor-α   and  interleukins,  thus  supporting PEA's role as a modulator of inflammation and pain.Activation  of PPAR-α  is neuroprotective  and, more gener- ally cytoprotective in a number of animal models.PEA  also  reduces  neurological  deficits  in  a  spinal  trauma model, via reduction of mast cell infiltration and activation. 

The concept of lipid N-acylethanolamines such as PEA acting in an autocoid manner to control mast cell activation was   first   proposed   by   the   Nobel   laureate   Rita   Levi- Montalcini  in 1993, using the acronym  ALIA (Auta- coid Local Injury Antagonism).Under this nomen- clature lipid amides like PEA are classified as ALIAmides, beingautocoids (regulating molecules) locally produced and acting locally. In this sense prostaglandins are also classified as autocoids. In the case of ALIAmide, these autocoids are synthesized in response to injury or inflammation, to coun- teract such pathology. The period 1993-2011 has seen nu- merous publications  dealing  with the modulatory  effects of PEA on mast cells. 

PEA affinity for PPAR-α, coupled with the widespread presence of this receptor in CNS microglia and astrocytes (which play a key role in the winding up phenomena, based on  peripheral  and  central  sensitization  provides  a strong underlying rationale for PEA application in the treat- ment of neuropathic pain. Further, PEA performed better in the so-called mice forced swimming test compared to  the  anti-depressant  fluoxetine. PEA  anti- inflammatory   action  counteracted  reactive  astrogliosis  in- duced by beta-amyloid peptide in a rodent model relevant for neurodegeneration,   most  probably   via  PPAR-α.In models of stroke, MS and other CNS trauma settings, PEA displayed  neuroprotective  properties.  At the  clinical  level,  in  Italy  for  example,  neurologists  have used this preclinical evidence as the impetus to treat patients suffering  from  a  variety  of  disorders,  from  MS  to  neuro- pathic pain.

 

PEA:  THE CLINICAL PERSPECTIVE 

Clinical research on PEA started in the 1960s and 1970s, especially  in  the  Czech  Republic.  [117-121]  PEA,  at  that time under the brandname ‘Impulsin’ was indicated for pre- vention of flu and respiratory diseases and immune system enhancement. Many years have since passed, with PEA be- ing subsequently explored in a variety of pain states: diabetic neuropathy, carpal tunnel syndrome, dental and temporo- mandibular joint pain, arthritic, postherpetic and chemother- apy-induced  neuropathic  pain. Below we will describe  data from a number  of human  clinical  pain trials. The main  re- sults  are  outlined  in  Table  1  and  have  been  discussed  by Keppel  Hesselink.Overall,  more  than  2000  patients have  been  successfully  treated  with  PEA,  and  no  adverse effects reported in any of the trials. 

Effect  of  PEA  on  Central and  Peripheral Neuropathic Pain 

A key dosing trial was performed  in Italy by Guida and colleagues. These   authors   carried   out   a placebo- controlled, double-blind, randomized study on 636 patients suffering from lumbosciatic pain (hernia and nerve root compression),   with  a  mean  Visual  Analogue  Pain  Scale


Table  1.    Analgesic  Effect of PEA on Chronic Pain: Overview of Clinical Trials. 

Indication    & Trial Design

Number of

Patients

PEA Dosage

Main Results

Ref

 

 

Peripheral Neuropathic Pain

Sciatic pain

 

 

Double blind, randomized, two   doses of PEA vs placebo

636

1st arm: 300mg/die x 3 weeks

2nd arm: 300mg/bid for weeks

Significant decrease of pain on

VAS (from 7 to 2)

[123]

Sciatic pain

 

 

Double blind, randomized, two   doses of PEA vs placebo

111

1st arm: 300mg/die for 3 weeks

2nd arm: 300mg/bid for weeks

Significant decrease in the duration of treatment with anti-inflammatory   and analgesic drugs

[142]

Pudendal neuralgia

 

 

Case Report

1

300mg/tid gradually de- creasing to 300mg/die for1 year

Resolution of chronic pelvic pain

[124]

Diabetic neuropathic pain

 

Open

30

300mg/bid for 60 days

Significant reduction of pain, burn-   ing, paraesthesia and numbness

[125]

Postoperative pain (surgical ex- traction of impacted lower third   molars)

 

Single-blind, randomized, split- mouth

30

300mg/bid for 6   days before and 9 days after surgery

Significant reduction in pain inten- sity

[126]

TMJ pain caused by osteoarthritis

Double blind randomized vs

NSAIDs

24

300mg at morning +

600mg at evening for7 days; followed by

300mg/bid for 7 days

Vs ibupfofen (600 mg/tid for 14 days)

Significant decrease of pain on VAS (from 7 to 0.7) an significant better maximum mouth opening compared to ibuprofen.

[127]

Diabetic neuropathy pain associ- ated with carpal tunnel syndrome

Group-controlled, randomized, PEA treatment v standard care

50

600 mg/bid for 60 days

Significant relief of pain. Significant improvement of neuro-   physiologic parameters

[131]

Carpal tunnel syndrome in dia- betic patients

Group-controlled, randomized vs   non-treated patients

40

600mg/bid for 60 days

Significant reduction of pain and functional status.

Significant improvement neuro-   physiologic parameters

[132]

Pain associated with carpal tunnel   syndrome

Group-controlled, randomized, two doses of PEA vs non-treated patients

26

1st arm: 300mg/bid for 30 days

2nd arm: 600mg/bid for 30 days

Significant dose-dependent reduc-   tion of pain and improvement of neurophysiologic parameters com-   pared with control group.

[133]

Neuropathic pain

Open

27

300mg/bid for 3   weeks followed by

300mg/die for 4 weeks

Significant reduction of pain and improvement of electrophysiologi-   cal parameters

[134]

Low back pain

Open (Combination therapy)

20

 

 

600mg/bid for 30 days

+

oxycodone (see text for dosage)

Significant decrease of pain on

VAS (from 7 to 2.5)

[136]


Table 1. Contd…. 

Indication    & Trial Design

Number of

Patients

PEA Dosage

Main Results

Ref

Neuropathic chronic pain (Dia- betic neuropathy and postherpetic neuralgia)

Open (Combination therapy)

30

Combination of Pre- gabalin+PEA 600mg bid for 45 days

+

pregabalin (see text for dosage)

Significant decrease of pain on

VAS, from 7.6 to 1.8

[137]

Various pain states (see text)

Open (Combination therapy)

517

600mg/bid for 3 weeks followed by 600mg/die for 4 weeks

+

Pregabalin and oxycodone

(see text)

61% decrease of mean pain score on

Numeric Rating Scale

[138]

Low back pain

Open (Combination therapy) Controlled (PEA +standard anal- gesics group vs standard analge- sics only)

81

600mg/bid for 3 weeks followed by

600mg/die for 4 weeks

+/-

Standard analgesics (see text)

Significant reduction of pain inten- sity in the PEA group compared to control group

[139]

Diabetic neuropathic pain

Group- controlled: Combination of PEA +Pregabalin  vs Pre- gabalin

74

600mg/bid for 10 days followed by

600mg/die for 20 days followed by

300mg/die for 30 days

Significantly higher rate of re- sponders (i.e., <60% decrease in pain score) in the combination   therapy group compared to pre- gabalin only group.

 

 

[140]

Sciatic pain

Group-controlled, randomized, combination of PEA +standard analgesic therapies vs standard analgesic therapies

85

300mg/bid for 30 days

Significant relief

of pain (scored both on VAS and Oswestry Low Back Pain Scale) in the PEA group compared to the   analgesic-only group.

[141]

 

Central Neuropathic Pain

Neuropathic pain and spasticity in   post-stroke patients

Open, controlled PEA + Physio-   ther() vs group treated with only   Physiother)

20

600mg/bid for 60 days followed by

600mg/die for 30 days

Significant decrease of pain and spasticity

[128]

Neuropathic pain associated with multiple sclerosis

Open

20

300mg/bid for 60 days

Significant decrease of neuropathic   pain

[129]

 

Chronic Pelvic Pain

Chronic pelvic pain associated with endometriosis/ dysmenor- rhoea /interstitial cystitis

Open

25

200mg/tid (+polydatin

20mg/tid) for 40 days

Significant reduction of pain on

VAS (from 6.8 to 1.7).

Significant decrease in the use of

NSAIDs.

[143]

Adolescent primary dysmenor-   rhoea

Open

20

400mg/bid (+ polydatin

40mg/bid)

for 6 months

70% decrease of pelvic pain

[144]

Chronic pelvic pain and dyspare- unia associated with endometri-   osis

Open (case series)

4

200mg/bid (+ polydatin

20mg/bid) for 3   months

Significant decrease of pelvic pain.   Significant decrease of dyspareunia. Significant reduction in the use of

analgesics.

[145]


Table 1. Contd…. 

Indication    & Trial Design

Number of

Patients

PEA Dosage

Main Results

Ref

Chronic pelvic pain associated with endometriosis

Double blind, ,randomized paral- lel-group, placebo-controlled

61

400mg/tid (+ 40mg/tid polydatin) for

3 months

Vs

celecoxib 200 mg/bid for

7 consecutive days

Significant decrease of cronic pelvic   pain, dysmenorrhoea and dyspare- unia in the PEA group compared to placebo group

[146]

Abbreviations: bid, bis in die = twice daily; die, daily; NSAIDs, non-steroidal anti-inflammatory drugs; tid, ter in die = three times daily; TMJ, temporomandibular joint; VAS, visual analogue pain scale..

(VAS) pain score at baseline of 6.5. The study consisted of three arms: placebo, PEA 300 mg/day and PEA 600 mg/day. The results after 3 weeks of treatment: placebo, decrease of pain from mean VAS 6.5 to mean VAS 4.5; 300 mg PEA,

6.5 to 3. 5; 600 mg PEA, 7.1 to VAS 2.1. PEA at the lower dose (300 mg) was significantly better compared to placebo, and higher dose PEA (600 mg) was significantly better com- pared  both  to  the  lower  dose  and  to  placebo.  No  relevant adverse  events  were  reported.  In  the  Youtube  and  Prezi added to this paper, further details on study outcome are pre- sented and discussed. 

Interestingly,  a case report on a 40-year-old healthy man with pudendal neuralgia (probably secondary to nerve com- pression) was recently published. The patient, who originally rated his pain at 8 on the 0–10 VAS, experienced  a signifi- cant improvement of neuralgia and associated symptoms on PEA, up to 900 mg/day. [124] 

The results of an open study performed on 30 patients suffering  from diabetic neuropathy  were recently  presented at the 2011 Congress of the European Shock Society. [125] Orally administered PEA (300 mg/twice daily for 60 days) significantly  reduced  the  clinical  sensory  symptoms (p<0.001), as scored by the Michigan Neuropathy Screening Instrument, Total Symptom Score, and Neuropathic Pain Symptom  Inventory.  In  particular,  PEA  treatment  signifi- cantly reduced the severity and frequency of pain, burning, paraesthesia and numbness. Moreover, the study clearly demonstrated  that  the  analgesic  effect  manifested  itself  as early as 30 days after treatment start, progressively increased over time and was maintained 1 month after treatment dis- continuation [125]. 

PEA reduced pain after surgical extraction of impacted lower third molars. A randomized, split-mouth, single-blind study was conducted on 30 patients between 18 and 30 years of age requiring lower third molar extraction. Patients un- derwent bilateral extractions in a randomized sequence, with one extraction being performed under PEA treatment (300 mg/twice daily for 15 days). Perceived postoperative pain, as measured on VAS, was significantly lower with PEA treat- ment compared to control (p<0.05) [126].

PEA was beneficial in osteoarthritic (OA) pain (which is considered a mixed pain, i.e., nociceptive and neuropathic components together) where it performed significantly better than a classical non-steroidal anti-inflammatory  drug. In this study a double-blind,  randomized  group-controlled  trial was


performed on 24 patients suffering from temporomandibular joint OA and divided in two groups: one (n=12) treated with PEA (300 mg in the morning plus 600 mg in the evening for

7 days, followed by 300 mg/twice daily for 7 more days); the second (n=12) received ibuprofen (600 mg/three times daily for two weeks). Spontaneous pain (on VAS) and maximum mouth opening were recorded and both resulted significantly better in the PEA-treated group compared to the ibuprofen- group [127]. 

Twenty  post-stroke   patients,  suffering   from  pain  and limb spasticity (i.e., hemiparesis, hemiplagia, paraparesis) received either rehabilitation  alone, or rehabilitation  therapy and PEA (600 mg/twice daily for 8 weeks, followed by 600 mg/sid for 4 adjunctive weeks). The results of this blind, randomized,  group-controlled  study  revealed  that PEA treatment  not only  reduced  pain  intensity  (as measured  by means of VAS) but also decreased spasticity as measured by a modified Ashworth scale. The difference between the two treatment  groups  were  statistically  significant  (p<0.0006). No side effects were reported [128]. 

A further  study  on the effect of PEA on central  neuro- pathic pain was performed on 20 patients (age 38-75 yrs) suffering  from  MS  and  presenting  neuropathic  pain  of the lower limbs, characterized by dysaesthesia along with allo- dynia, paraesthesia, cramping pain and burning feet. Pain severity was evaluated by means VAS and was significantly reduced in14 out of 20 patients (p=0.001) after 2 month- treatment with PEA 600mg/day [129]. 

Lastly, it is interesting  to note that in an open observa- tional study, performed on 8 patients with facial postherpetic neuralgia, a topical preparation containing PEA (twice daily applications to the affected site for two to four weeks) suc- cessfully controlled postherpetic pain. Five patients (62.5 %) experienced a mean pain reduction on VAS of 87.8 %. The therapy was well-tolerated by all patients, with no unpleasant sensations or adverse events [130].

 

Effect of PEA on Electrophysiologic Changes in neuro- pathic Patients 

In addition to clinical signs (i.e., pain, spasticity) also electrophysiologic  deficits  improved  under  PEA  treatment. A group-controlled, randomized study was performed in 50 diabetic patients suffering from carpal tunnel syndrome with moderate   pain  [131].  The  control  group  (standard   care, n=25) was tested against PEA (600 mg/twice daily, n=25). A

significant  improvement  in  pain  at  endpoint  in  the  PEA- treated group compared to the control group was noted (p <

0.0001).   Moreover,   the  neurophysiologic   parameters   as- sessed (sensory conduction velocity and nerve distal motor latency)  improved  with  PEA  treatment.  No  relevant  side- effects were documented. 

In a more recent study from the same group [132], 40 diabetic patients with mild-to-moderate carpal tunnel syn- drome were treated orally with PEA (600 mg/twice daily for

2 months). These patients presented a significantly decreased pain severity, self-reported symptom severity and functional status (the Boston Carpal Tunnel Questionnaire) and electro- physiologic parameters, as early as 1 month after the begin- ning of PEA treatment. 

A further randomized, group-controlled  study on patients with carpal tunnel syndrome and clear neurophysiologic ab- normalities and pain was performed with a three-arm design: control  (no treatment  during  the study  period,  n=12),  PEA (300  mg/twice  daily,  n=6),  PEA  300  mg/four  times  daily (n=8). There was a significant improvement in neurophysi- ologic parameters  (distal motor latency)  in both dose arms, with  the  higher  dose  being  more  effective  [133].  Further, there  was  a clinically  relevant  decrease  in pain  and  fewer signs of Tinel in treatment  groups 30 days on. No relevant side-effects were noted [133]. 

In a preliminary open study on 27 patients with painful neuropathy who were either drug naïve or non-responders  to other drugs, PEA (300mg/twice  daily for 3 weeks, followed by 300mg/daily  for 4 weeks) appeared improve nerve func- tion and reduce neuropathic pain. In this study pain was evaluated on an 11-point numerical rating scale, while nerve function  was assessed  by nerve conduction  (for non- nociceptive fibres) or laser evoked potentials (for nociceptive fibres). PEA treatment increased the amplitude of sural and ulnar  sensory  nerve  action  potentials,  and  decreased  the mean pain score. After treatment, the sensory index (i.e., the mean value of the afferent pathway-related neural responses) was higher compared  to that at baseline. All results reached statistical significance (p<0.05) [134]. 

Finally,  this  same  group  of  investigators  assessed  the effect of PEA on pain and nerve function in patients with chemotherapy-induced painful neuropathy [135]. Twenty patients underwent thalidomide (50-200 mg daily) and bortezomib (1.3 mg/m2 twice a week) treatment for Kahler's disease  (multiple  myeloma).  Chemotherapeutic  agent- induced neurotoxicity, evidenced as neuropathic pain devel- opment and nerve function decline, occurred during the first

3  months.  Treatment  with  PEA  (300  mg/twice  daily)  was carried out between months 3-5. Patients entering the study all suffered from neuropathic pain, and scored at least 4 on Bouhassira’s DN4 screening tool for neuropathic pain. All patients were evaluated before and after the two-month treatment with PEA. Parameters measured by blinded ob- servers were: (i) pain and warmth thresholds; (ii) motor and sensory nerve fibre function; (iii) laser-evoked potentials.

Nerve conduction  studies consisted  of sensory nerve ac- tion potentials from sural and ulnar nerves, as well as com- pound   motor   action   potentials   from  peroneal   and  ulnar nerves.


 

Pain as measured on the VAS decreased from 4.5 ± 1.2 to

3.4 ± 1.0. All neurophysiologic  measures-assessing  Aα, Aß, and Aò fibre functionality  significantly  improved  compared to baseline, while all patient continued their borte- zomib/thalidomide  therapy (P < 0.05). None of the variables, however,  returned  to  normal.  Had  the  patients  not  been treated, nerve function  would have deteriorated  further and pain increased, making it necessary to stop or reduce chemo- therapy.

Although a placebo effect might play a role in the reduction of pain-intensity, the changes in neurophysiologic measures indicate that PEA exerted a neuroprotective  effect on myeli- nated nerve fibers. Without dose-reduction  of chemotherapy one  would  not  expect  an  improvement  between  months  3 and 5. On the contrary, further deterioration would be ex- pected.[135] The authors concluded: “ PEA, possibly by moderating   mast   cell   hyperactivity,   relieved   conduction blocks secondary to endoneural edema. In a severe condition such  as  painful  neuropathy  associated  with  multiple  mye- loma and chemotherapy,  a safe substance such as PEA pro- vides significant restoration of nerve function”[135].

 

PEA May Synergize  with Classical  Analgesic  Drugs 

A number of clinical trials have described a synergistic action between PEA and other analgesics, e.g. opiates and antiepileptic drugs used for neuropathic pain. The first ex- ample is the report by Desio, [136] who conducted  an open study in 20 patients suffering from chronic pain and unre- sponsive to a variety of analgesics. In particular, patients suffered  from low  back  pain  secondary  to  collapsed  verte- brae, lumbar spinal stenosis syndrome and slipped discs. Treatment  regime  was as follows:  oxycodone  daily  (5 mg) for 5 days, followed by 5 mg/twice daily for 25 days; in ad- dition,  PEA  (600  mg)  was  given  twice  daily  for  30  days. Pain score decreased from a mean of VAS 7 at entry to mean VAS 2.5 at day 30 (p<0.001). Moreover, pain was observed

to decrease  as early  as the 10th  day  of treatment,  and  was

maximally reduced at the end of treatment (day 30). No ad- verse events and no drug-drug interactions were observed. 

In a further trial by the same author, PEA was success- fully associated to pregabalin in a 45-day treatment of 30 patients suffering from chronic pain due to diabetic neuropa- thy or postherpetic  neuralgia.  [137]  The treatment  regimen was  as  follows:  PEA  (600  mg/twice  daily)  for  the  whole study duration, associated with pregabalin 75 mg/twice daily for 10 days, followed by a daily dose of 75 mg in the morn- ing plus 150 mg in the evening  for the next 10 days; then

150  mg/twice  daily  for  a further  10 days,  and  finally  200

mg/twice  daily  for  the remaining  15 days.  The severity  of pain, as measured using VAS, significantly decreased during the  duration   of  the  study   (45   days),   from   7.9   to   1.8 (p<0.0001).

A preliminary report on chronic pain due to different conditions also showed that patients benefited from PEA as an adjunct to classical analgesic drugs. The study was per- formed on 517 patients, suffering from radiculopathy  and/or osteoarthritis  (64.6%),  failed  back  surgery  syndrome (12.77%), postherpetic neuralgia (5.8%), diabetic neuropathy (4.64%), oncologic pain (3.29%), or other pain states (e.g., trigeminal neuralgia, post-traumatic neuropathy; 8.9%). PEA (600 mg/twice daily for 21 days followed by 600 mg/day for a further 30 days) was added to a fixed dose of pregabalin and oxycodone hydrochloride. Pain was scored at the begin- ning and end of treatment (51 days) by means of a Numeric Rating Scale. A 61.1% mean decrease of pain was recorded [138].

The efficacy of PEA as part of a multimodal analgesic therapy in patients with low back pain was presented at the Naples Pain Conference  in 2010 [139]. Eighty-one  patients were divided in two groups: the first group (n=41) received PEA  (600  mg/twice  daily  for  21  days  followed  by  600 mg/day for the remaining 30 days) on top of standard anal- gesics  (pregabalin,   gabapentin,   amitriptyline,   duloxetine); the second group received standard  analgesics  only. At day

51 (endpoint)  PEA-treated  patients had less pain compared to standard care (p<0.05). No side effects or drug-drug inter- actions were observed.

More recently, data on the synergism  of PEA combined with pregabalin were presented at the 34th AISD Congress by Adiletta  and  coworkers  [140].  The  authors  performed  an open  study  on  74  patients  suffering  from  diabetic  neuro- pathic pain divided  in two groups: pregabalin  monotherapy

(titrated up to 600 mg/day) or pregabalin with added PEA at

a decreasing  dose from 600 mg/twice daily to 300 mg/day. Pain severity  was evaluated  by means of Brief Pain Inven- tory; the response to treatment was considered to be at least a

60% decrease in pain score. There was a significantly higher rate of response to pregabalin plus PEA compared to pre- gabalin only (73% responders versus 40%) p<0.01. No side effects or interactions were observed. [140] 

In a group-controlled, randomized study performed on 85 patients suffering from lumbosciatic pain, a 30-day treatment associating PEA (600 mg/day) to standard analgesic therapy was statistically  better in relieving pain than the same dura- tion treatment with analgesics alone. This was true for pain evaluations with either VAS or the Oswestry Low Back Pain Scale [141]. 

Lastly, a randomized, double-blind  study, performed  us- ing the same design and dose regimen as Guida and collabo- rators [123] showed  a statistically  significant  decrease (p<0.05) in the duration of treatment with anti-inflammatory and/or analgesic drugs in the PEA-treated group compared to the placebo group [142].

Overall, these results suggest that PEA may exert a spar- ing effect on drugs classically used in chronic pain manage- ment.

 

Effect of PEA on Visceral  Pain 

The results presented so far clearly illustrate that PEA benefits somatic pain, from neuropathic to postoperative and mixed pain. Interestingly,  also chronic pelvic pain, i.e. vis- ceral pain, has been shown to respond to PEA. In particular, when combined with polydatin (i.e. the natural glucoside of resveratrol  with  anti-inflammatory  and antioxidant  effects), in the ratio 10:1, PEA exerted  an important relief of pelvic pain.

In an open study of 25 female patients suffering from endometriosis (n=15), interstitial cystitis (n=6) and dysme- norrhea (n=4) a 60 day-treatment with PEA (200 mg/3 times a day) plus polydatin (20 mg/3 times a day) resulted in a significant  decrease  of  pain,  with  a  VAS  score  reduction


from  6.8  (before  treatment)  to 3.2  (after  30 days)  and  1.7 (after 60 days - study end). Moreover, the combined  use of non-steroidal  anti-inflammatory  drugs  significantly  de- creased [143].

A further preliminary study on the effect of PEA on dysmenorrhea was presented at the Pediatric and Adolescent Gynecology  Congress  2010  [144]. Twenty  adolescent  girls were found to benefit from PEA + polydatin treatment, with a 70% reduction of dysmenorrhea  after a 6-month treatment (PEA 200 mg + polydatin 20 mg/3 times a day).

A case series on chronic pelvic pain successfully treated with PEA was recently published. Four patients presenting a endometriosis-related   pain  intensity  >5  on  VAS  were  en- rolled and monitored during 3 months of the following treatment: oral PEA (200 mg) and polydatin (20 mg), twice daily for 90 days. Chronic pelvic pain intensity due to endo- metriosis and deep dyspareunia, dyschezia, dysuria or dys- menorrhoea  was  evaluated  on VAS  at baseline  and during the programmed  follow-up after 1, 2 and 3 months of treat- ment. All patients experienced pain relief as early as 1 month after starting  treatment  (p < 0.0069).  For dyspareunia  there was a significant reduction  at day 30, which remained  con- stant until the end of the study (p < 0.0132). The reduction in pain intensity was paralleled by a statistically significant (p <

0.0176) reduction in analgesics use [145]. 

In a randomized, double-blind, parallel-group, placebo- controlled clinical trial on 61subjects with endometriosis, patients were submitted to a first line laparoscopic conserva- tive surgery and randomized into 3 groups: group A (n = 21) PEA (400 mg) +polydatin (40 mg) twice daily for 3 months; group B (n = 20)placebo  for 3 months; group C (n = 20) a single course of Celecoxib 200 mg twice daily for 7 consecu- tive days. A marked decrease in dysmenorrhoea, dyspareunia and pelvic pain was observed, with the combination of PEA and polydatin significantly more effective than placebo (p <

0.001). The authors stated that “this safe association  shows an optimal control of pain and could be used in patients who are unable to receive other therapies” [146].

 

DOSE RECOMMENDATIONS OF PEA 

The  results  of  clinical  trials  with  PEA  in  human  pain states,  together  with  current  preclinical  data  suggest  that PEA   might   possess   neuro-regenerative   properties   [147]. PEA is available for clinical use and is marketed by the Ital- ian company Epitech under the trade name Normast@ (for neuropathic pain) and Pelvilen@ (for pelvic pain) [52]. Two different formulations have been developed, an ultra- micronized  formulation  of PEA for sublingual use, contain- ing 600 mg, and tablets of 300 or 600 mg PEA. Combination of PEA with opioids, gabapentoids and antidepressants for treating  chronic  and  neuropathic  pain  is  possible,  and  no drug-drug interactions have been reported. [148] Synergistic effects of PEA with pregabaline and oxycodone have been described, as discussed above. [136-142] 

Based on our knowledge to date, recommended starting treatment  dose  for  PEA  is:  twice  daily  600  mg  ultrami- cronized PEA, in 600 mg sublingual sachets, 10 days or, in the case of central  neuropathic  pain  20-30  days.  After  the initial loading  dose phase, patients  can be treated with 600 mg tablets twice daily. If pain is reduced at least 30-50%, a lower dose can be selected,  i.e., 300 mg/twice daily. In the case of a relapse under tablet regime, transfer patients to 600 mg Normast sublingual sachets for at least 20 days. Some patients, especially those with central neuropathic pain may respond better to sublingual sachets, but relapse on tablets.

Physicians wishing to consult the author can do so by sending an email to: jan@neuropathie.nu 

An English presentation on this topic for Italian pain spe- cialists, presented at the 2011 congress of ‘La società italiana di anestesia analgesia rianimazione e terapia intensiva (SIAARTI)  can be found (following  a 1.5 minute introduc- tion in Italian) on: http://www.youtube.com/watch?v=3 wgdwcijCt0 

Illustration for this article as a Prezi:

http://prezi.com/zgzjdoudele-/glia-modulator-is-breakthrough- in-treatment-chronic-and-neuropathic-pain/

 

CONFLICT OF INTEREST 

None declared.

ACKNOWLEDGEMENT 

None declared. 

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