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Medical Hypotheses 73 (2009) 927–929 Contents lists available at ScienceDirect Medical Hypotheses Post herpetic neuralgia, schwann cell activation and vitamin D The Auckland Regional Pain Service, FRACS, 10 Owens Rd., Epsom, Auckland 1023, New Zealand While the underlying pathophysiology of herpes zoster infection has been well characterised, many of the Received 17 June 2009 mechanisms relating to the subsequent development of post herpetic neuralgia (PHN) remain uncertain.
Accepted 18 June 2009 The dorsal horn atrophy and reduction in skin innervation seen in PHN patients does not adequatelyexplain many clinical features or the efficacy of a number of topical treatments. In the central nervoussystem the glia, their receptors and their secreted signalling factors are now known to have a major influ-ence on neural function. In the peripheral nervous system, schwann cell activation in response to infec-tion and trauma releases a number of neuroexcitatory substances. Activation of the nervi nervorum in theperipheral nervous system also leads to the release of calcitonin gene related peptide, substance P andnitric oxide. Schwann cell and/or nervi nervorum activation could be an additional mechanism of paingeneration in PHN. Such a paradigm shift would mean that drugs useful in the treatment of glial cell acti-vation such as naloxone, naltrexone, minocycline, pentoxifyllline, propentofylline, AV411 (ibudilast) andinterleukin 10 could be useful in PHN. These drugs could be used systemically or even topically. Highdose topical vitamin D would appear to offer particular promise because vitamin D has the ability to bothreduce glial inflammation and reduce nitric oxide production.
Ó 2009 Elsevier Ltd. All rights reserved.
and central mechanisms. Traditional gate-control pain theory tea-ches that reduced sensory input from large A-b fibre nerves in the The management of post herpetic neuralgia (PHN) following the skin then allows increased firing from C and A-d nerves reaching recurrence of a herpes zoster viral infection can be challenging. The the dorsal horn of the spinal cord which in turn ‘‘opens the gate" underlying pathophysiology of the initial herpes zoster (HZ) reac- to a deafferentation type pain. Degeneration of peripheral neurons tivation has been well characterized [1]. Initially viral replication with resultant hyperexcitability of spinal cord neurons has also causes inflammation in the dorsal root ganglion (DRG) with conse- been posited. Dorsal horn atrophy is a major feature of PHN pa- quent infection of the corresponding nerves and skin dermatome.
tients [2,7]. A reduction in skin innervation density using axonal Inflammatory processes can involve the dorsal horn of the spinal markers has also been shown to be a feature of HZ [3,4], and these cord [2]. Necrosis and scarring of the DRG is followed by secondary changes are more dramatic in patients with PHN [3]. Histamine re- degeneration and fibrosis of the associated motor and sensory sponses are reduced or abolished within areas of allodynia and nerve roots. Axonal and myelin damage extends peripherally from impairment of C nerve fibre function has been correlated with the DRG. A decrease in the number of nerve endings in the associ- the intensity of post herpetic pain [8].
ated skin dermatome occurs [3,4].
On the other hand, axonal and myelin loss in the peripheral A number of PHN syndromes can then develop: nerves is similar regardless of whether patients have PHN or not[9]. No difference in substance P, calcitonin gene related peptide, – A constant, spontaneous, deep-aching, or burning pain.
a norepinephrine marker or in opioid receptor binding sites has – A brief recurrent, piercing or electrical-shock-type pain often been found between affected and non-affected spinal cord levels described as a spasmodic shooting, tic-like pain.
[10]. Moreover the severity of allodynic pain has been correlated – Allodynia (pain occurring in response to normally innocuous with preservation of thermal sensory function [11]. A significant stimuli) and hyperalgesia [5,6].
correlation has been found between the intensity of ongoing painand mechanical allodynia in patients with short lasting (<1 year) Chronic itch can also be problematic in some patients [4].
PHN, but not in patients with long lasting PHN [12]. Oaklander A single mechanism unifying these pain syndromes may prove et al. [13] have also shown bilateral segmental damage to primary elusive. The pathophysiology of PHN may involve both peripheral sensory neurons with unilateral HZ. Changes in contralateral unaf-fected skin innervation in patients with PHN correlate with thepresence and severity of pain, yet these patients report no pain * Tel.: +64 9 631 0475; fax: +64 9 631 0478.
E-mail address: [email protected] on the contralateral side.
0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2009.06.039 Author's personal copy
J. Bartley / Medical Hypotheses 73 (2009) 927–929 Despite the severity of the underlying structural neurological lidocaine and prilocaine, is also beneficial in some patients with changes, many PHN patients improve by themselves. One prospec- PHN [28]. Both agents are thought to block upregulated nerve so- tive long-term follow-up study reported that at one month 19% of dium channels thereby reducing pain. These agents could also the patients had pain, at 3 months 7% and at one year 3%. Once a block the activated Na+ channels in Schwann cells [22] after nerve patient becomes pain free after a zoster episode there is practically no risk of pain recurrence [14]. Another prospective community Capsaicin cream has also been shown to be beneficial in both study reported that at 6 weeks 30% of the patients had pain, at PHN as well as diabetic neuralgia [30], however the cream induces 3 months 27%, at 6 months 16% and at one year 9% [15]. The epide- a burning sensation in the skin which makes it difficult to use. This miological data indicates that despite extensive neural damage not has been interpreted as evidence that nociceptive peripheral axons all patients proceed to PHN, and the damage is not irreversible.
contribute to PHN pain and allodynia. Capsaicin reduces the levelsof substance P, a potent pro-inflammatory peptide, and possibly Schwann cell activation other neurotransmitters in peripheral sensory nerves. Reductionof substance P levels would also reduce schwann cell and nervi Traditional pain research has focused largely on the neurons nervorum inflammation. A topical aspirin/diethyl ether mixture and the transmission of neural signals. In the central nervous sys- has also been shown to be useful in the treatment of PHN [31].
tem the glia (oligodendrocytes and astrocytes), their receptors and Similar results have been noted with aspirin in chloroform [32].
their secreted signalling factors also influence neural function. Per- The analgesic mechanisms remain unexplained using conventional sisting glial inflammation has been implicated in the initiation and neurological pain theory. However a reduction in schwann cell and maintenance of a number of pain states [16]. In the peripheral ner- possibly nervi nervorum inflammation offers a potential mecha- vous system the schwann cells and the satellite cells in the DRG are nism. Aspirin influences cyclooxygenase mechanisms, which have now recognized as ‘‘peripheral glia" sharing many of the character- been implicated in glial cell activation [17].
istics with oligodendrocytes and astrocytes in the CNS (17). Injuryto a myelinated axon results in Schwann and satellite cell activa- tion and the release of a number of neuroexcitatory substances,including TNF-a [18–21]. Nerve injury as well as increasing the Sunlight, particularly ultraviolet B rays, can damage skin setting number of Na+ channels in injured nerves may also increase in up an inflammatory reaction. When this is excessive, we experi- Na+ channels in schwann cells [22]. The release of these inflamma- ence this as sunburn with a corresponding hyperalgesia. The skin tory mediators is blocked by treatment with anti-inflammatory has mechanisms to counter this. The skin creates molecules called drugs including dexamethasone [23] and thalidomide [24]. Inter- proopiomelanocortin derived peptides, which then break down estingly in nerve ventral root transection, TNF-a concentrations into other hormones, which include melanocyte stimulating hor- on both sides of the spinal dorsal horn are increased [24]. This mones (MSH), and b-endorphins which act as a natural painkillers might be a factor in the as yet unexplained reduced innervation [33]. MSH has powerful anti-inflammatory effects. Alpha-MSH on the contralateral side seen in patients with PHN [13].
downregulates the production of proinflammatory and immuno-modulating cytokines as well upregulating the production of thecytokine synthesis inhibitor IL-10 [34] which is important in Nervi and vasa nervorum reducing glial inflammation. Vitamin D also has similar anti-inflammatory actions. Vitamin D also has an important role in All peripheral nerves have an intrinsic nerve and vascular sup- astrocyte ‘‘detoxification" pathways. Vitamin D receptors have ply. All layers of the nerve are innervated and have a thin, but been located within glial cells. Vitamin D inhibits the synthesis potentially important plexus of nociceptors. The ‘‘nervi nervorum" of inducible nitric oxide and increases glutathione and c-glutamyl have the potential to induce neurogenic inflammation [25–27].
peptidase levels in astrocytes. Gamma-glutamyl peptidase is Peripheral nerve injury leads to the release of calcitonin gene re- thought to participate in the scavenging of reactive oxygen species lated peptide, substance P and nitric oxide from the nervi nervo- [35]. Vitamin D could potentially reduce Schwann cell inflamma- rum which upregulates the vascular permeability of the vasa tion. UVB phototherapy in the acute stage of zoster rash reduces nervorum and neighbouring blood vessels [26]. Activation of the the incidence and severity of PHN, however treatment of PHN with nervi nervorum has been implicated in peripheral nerve pain [27].
UVB radiation after 3 months does not have a significant beneficialeffect.
Current treatment modalities Vitamin D also upregulates nerve growth factor gene expression [35]. Nerve growth factor is produced both in keratinocytes and Psychotropic drugs and anticonvulsant medications are a cor- Schwann cells. In diabetic peripheral neuropathy there is degener- nerstone of PHN treatment. Opioid medication has also been advo- ation of Schwann cells and myelinated neuronal fibres as well as a cated [28]. Tricyclic antidepressants have been utilized either loss of cells within the DRG [36]. The pathological findings are sim- alone, or in combination with other therapies including neurolep- ilar to PHN. Animal models of diabetic neuropathy have shown tic agents. More recently, gabapentin and pregabalin have been nerve growth factor effective against measures of neuropathy.
shown to be effective. However the elderly, a group of patients typ- Phase 1–2 and HIV trials have demonstrated improvements in pain ically affected by PHN, tolerate these medications poorly and the symptoms when recombinant human nerve growth factor has long-term efficacy of these interventions remains unknown [28].
been used, however the phase 3 trial did not demonstrate any ther- The clinical reality is that as many as half of all patients fail to re- apeutic benefit. The recombinant human nerve growth factor was spond to these medications (alone or in combination) or cannot delivered by subcutaneous injections [37].
tolerate their side effects [29].
Both PHN and diabetic neuropathy respond to topical capsaicin The efficacy of a number of topical agents indicates that periph- cream. High dose oral Vitamin D has been shown to be effective in eral as well as central mechanisms are important in PHN. Topical the treatment of diabetic neuropathy [38]. Quantitative sensory lignocaine when used as a 5% gel under an occlusive dressing par- testing reveals decreased pain sensibility (with or without de- tially reduces pain and allodynia in PHN. Blood lidocaine level creased touch sensibility). The author has also had one vitamin D measurements indicate minimal systemic absorption. EMLA deficient patient whose post herpetic neuralgia pain was signifi- cream, an acronym for eutectic mixture of the local anaesthetics cantly reduced when he was treated for his vitamin D deficiency.
Author's personal copy
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