In diabetes mellitus low grade inflammation is one of the key pathogenetic factors, leading to many of its complications and neuropathic pain. Such inflammatory processes are also documented in skin tissue, where peripheral sensitization originates. We will discuss new findings pointing out that there are multiple important targets in the skin to be influenced by topical analgesics alone or in combination with anti-inflammatory agents. By specifically targeting the skin, analgesia seems possible, effective and safe and thus topical analgesic creams may become an important new treatment modality for the treatment of neuropathic pain. We will present a case and discuss a new rational fundament for the treatment of diabetic neuropathic pain via local mechanisms in the skin, using an analgesic cream consisting of baclofen and the anti-inflammatory agent palmitoylethanolamide
topical, transdermal, diabetes, inflammation, autacoids, analgesics, neuropathic, pain
Since the end of last century topical analgesics are increasingly explored and discussed as serious options for treating different classes of pain [1-5]. Such formulations are reported to have a number of advantages over classical painkillers such as absence of troublesome side-effects, low propensity for drug-drug interactions, and low risks for accumulation in poor metabolizers.
Analgesic and anti-inflammatory agents used in compounded topical creams can be selected based on having a multitude of effects at different targets in the skin, thus influencing various biological functions related to nociception and immunity . Keratinocytes for instance are in close functional contact with sensory afferent nerves. In response to noxious stimuli, keratinocytes release various growth factors and pro-inflammatory cytokines [7-9]. These molecules trigger the expression of nociceptive relevant receptors, such as the adrenoceptor, on nerve fibers and other cells in the injured tissue [10,11]. Autonomic nerve endings in the skin release norepinephrine, whereas sensory nerve fibers release neuropeptides . This again leads to a further production of pro-inflammatory cytokines, such as interleukin-6, creating a pain-inflammation sensitization cascade . The cross-talk between nerve endings, keratinocytes and other cells of the skin make the skin a valuable target for compounded multi-target analgesic creams.
In our clinic for neuropathic pain we see exclusively patients suffering from neuropathic pain, who usually are non-responders to classical oral neuropathic pain medication, such as amitriptyline, duloxetine, pregabalin, gabapentin and carbamazepine. Most patients cannot tolerate these classes of medication due to severe side effects, or the prescribed medication does not result in adequate analgesia. Since 2010 we have started to develop a variety of compounded creams leading in general to good responses in refractory patients, without serious side effects.
In November 2015, a 71-year-old woman with diabetes mellitus type II since 2005, came to our Institute for Neuropathic Pain with complaints of neuropathic pain in both legs up to her knees. In 2009 neuropathic pain started in both her feet, and at the first visit was characterized as pins and needles, burning and painful cold with numbness in the same area. She scored her pain as 8 on the 11-point numerical rating scale (NRS). Pain worsened during the day. Her glucose level was under control with gliclazide 80 mg twice daily, metformin 500 gm trice daily and a short acting insulin 36 unit per day. Oral amitriptyline and pregabaline resulted in too much side effects, and patient felt quite drowsy. Physical examination revealed the following: lowered knee tendon reflexes, absent Achilles tendon reflexes, disturbed warmth/cold sensation up to 15 cm below her knees, absence of vibratory sensation in malleoli and metatarsalia of both feet, hypesthesia for touch and pinprick and no allodynia. We tested clonidine 0.2% cream and baclofen 5% cream in a cream base including palmitoylethanolamide 1%. After 20 minutes the patient experienced 50% pain reduction of her pain at the area were baclofen 5% was applied. Clonidine 0.2% was less effective. Following this positive response-test we prescribed baclofen 5% cream with the instruction to apply the cream up to 4 times daily, depending on the duration of the analgesic effect. One month later she reported that all pain sensations were disappeared due to the application of baclofen 5%-palmitoylethanolamide 1% cream two times daily. The only remaining sensation was numbness. The patient is using this cream already for 7 months in a row, without experiencing any side effects.
Low grade peripheral inflammation in diabetes
Low grade inflammation is one of the key pathogenetic factors in diabetes, and recently an identified therapeutic target for diabetes mellitus [14,15]. Such chronic low grade inflammation is recognized also to play a role in other axonal neuropathies (e.g. thin fiber neuropathy, sarcoidosis-associated neuropathy) and post-infectious neuropathies [16,17]. Low grade inflammation has even been identified in Charcot-Marie-Tooth neuropathies as a disease amplifier, and is thus seen as a new target also for this specific disease .
The cell surface enzyme neutral endopeptidase, which degrades substance P, was used as a peripheral marker for inflammation in diabetic skin. This marker was found to be significantly more frequent in skin of diabetes patients compared to normal skin . The authors pointed out that elevated levels of this marker in the skin may contribute to enhanced neuro-inflammatory signaling . Low grade inflammatory processes may subsequently lead to peripheral nerve damage, enhance transmitter release within the spinal cord and induce central sensitization . This sequence of events, leading from peripheral derangements to central wind-up and sensitization, might also plays a role in the chronification of acute pain as seen in post-surgical pain syndromes.
Skin matters in diabetic neuropathic pain
In the epidermis we find an intimate interplay between many non-neuronal cells, such as keratinocytes, with various dermal immunocompetent cells, such as dendritic cells, gamma-delta T cells and mast cells, as well as with the nerve endings in the skin [21,22]. Sensory nerves extend into the epidermis and make close contact with keratinocytes via membrane-membrane apposition . Non-neuronal cells of the skin can release many neuroactive substances, which can contribute to the initial transduction process in the nerve endings [24,25]. Non-neuronal cells, such as the mast cells and keratinocytes, cross-talk with these nerve endings. Nociceptors terminate in the skin as free nerve endings and can directly contact injured tissue, which all serve as a sensory receptors of the injury . In skin tissue we also find a great variety of receptors and inflammatory markers which play a role in nociception such as the adrenoceptors, voltage-gated sodium channels, temperature-sensitive transient receptor potential ion channels, substance P and inflammatory markers such as caspase-1 and interleukin receptors. Clearly this is all in support for topical treatment: ‘Skin matters in pain treatment!’ .
Palmitoylethanolamide as a mast cell modulator
Skin keratinocytes express neurotrophic growth factor (NGF) after loss of contact with the axon, as in painful diabetic neuropathy, and subsequently nerve fibers in skin exposed to excess of NGF are triggering hyperalgesia . Professor Rita Levi-Montalcini, who was awarded the Nobel prize for her work in the field of NGF, pointed out that certain immune-competent cells in the skin producing NGF, such as the mast cells, can be targets for local modulation with autacoids. She proved her hypothesis by administering the autacoid palmitoylethanonolamide in various animal models and could demonstrate this compound could indeed reduce the mast cell production of NGF. These experiments led to the use of palmitoylethanolamide in mast cell related disorders as well as in neuropathic pain [29-31]. Palmitoylethanolamide is currently available as a food supplement (400 mg capsules) as well as a topical cream (1%) .
Given the above lines of argumentation, we feel topical treatment of neuropathic pain may bring relief of pain, through influencing multiple targets in the skin, related to nociception and inflammation. These topical agents can be used either as monotherapy or as part of multi-model therapy. We compounded different analgesic and anti-inflammatory agents in a cream base and currently explore the value of such analgesics and palmitoylethanolamide in these creams. Doing so we have developed a variety of compounded creams in one specific base. This base is optimally suited to contain both lipophilic as well as hydrophilic agents, enabling mixing various analgesic components in order to create a multi-target topical cream. We have successfully combined amitriptyline, ketamine, clonidine, baclofen with the autacoid and anti-inflammatory agent palmitoylethanolamide and reached therapeutic synergies [5,33-36].
The skin needs to be recognized as an important therapeutic inroad in treating neuropathic pain via the many pathogenetic mechanisms we identified and discussed. Both anti-inflammatory as well as analgesic agents can serve in topical formulations to target and influence the various components of the skin in diabetic neuropathic pain. Topical creams might contribute significantly to the treatment of neuropathic pain in diabetes mellitus.
The authors report no conflict of interest.
- Argoff CE (2004) Targeted peripheral analgesics therapy for neuropathic pain. Curr Pain Headache Rep 8: 199-204. [Crossref]
- de Leon-Casasola OA (2007) Multimodal approaches to the management of neuropathic pain: the role of topical analgesia. J Pain Symptom Manage 33: 356-364. [Crossref]
- Sawynok J (2014) Topical analgesics for neuropathic pain in the elderly: current and future prospects. Drugs Aging 31: 853-862. [Crossref]
- Kopsky DJ, Keppel Hesselink JM, Bhaskar A, Hariton G, Romanenko V, et al. (2015) Analgesic effects of topical ketamine. Minerva Anestesiol 81: 440-449. [Crossref]
- Kopsky DJ, Hesselink JM (2012) High doses of topical amitriptyline in neuropathic pain: two cases and literature review. Pain Pract 12: 148-153. [Crossref]
- Irving G (2010) Targeting the skin for treating peripheral neuropathic pain (Industry Symposium Sponsored by Astellas). European Journal of Pain Supplements 4: 19-19.
- Pang Z, Sakamoto T, Tiwari V, Kim YS, Yang F, et al. (2015) Selective keratinocyte stimulation is sufficient to evoke nociception in mice. Pain 156: 656-665. [Crossref]
- Sloniecka M, Le Roux S, Boman P, Bystrom B, Zhou Q, et al. (2015) Expression profiles of neuropeptides, neurotransmitters, and their receptors in human keratocytes in vitro and in situ. PLoS One 10: e0134157. [Crossref]
- Ritter-Jones M, Najjar S, Albers KM (2016) Keratinocytes as modulators of sensory afferent firing. Pain 157: 786-787. [Crossref]
- Drummond PD, Dawson LF, Finch PM, Drummond ES, Wood FM, et al. (2015) Up-regulation of cutaneous α1-adrenoceptors after a burn. Burns 41: 1227-1234. [Crossref]
- Dawson LF, Phillips JK, Finch PM, Inglis JJ, Drummond PD (2011) Expression of α1-adrenoceptors on peripheral nociceptive neurons. Neuroscience 175: 300-314. [Crossref]
- Di Comite G, Grazia Sabbadini M, Corti A, Rovere-Querini P, Manfredi AA (2007) Conversation galante: how the immune and the neuroendocrine systems talk to each other. Autoimmun Rev 7: 23-29.
- Drummond PD (2014) Neuronal changes resulting in up-regulation of alpha-1 adrenoceptors after peripheral nerve injury. Neural Regen Res 9: 1337-1340. [Crossref]
- Morettini M, Storm F, Sacchetti M, Cappozzo A, Mazzà C (2015) Effects of walking on low-grade inflammation and their implications for Type 2 Diabetes. Prev Med Rep 2: 538-547. [Crossref]
- Apostolopoulos V, de Courten MP, Stojanovska L, Blatch GL, Tangalakis K, et al. (2016) The complex immunological and inflammatory network of adipose tissue in obesity. Mol Nutr Food Res 60: 43-57. [Crossref]
- Albers JW, Pop-Busui R (2014) Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. Curr Neurol Neurosci Rep 14: 473. [Crossref]
- Bagnato F, Stern BJ (2015) Neurosarcoidosis: diagnosis, therapy and biomarkers. Expert Rev Neurother 15: 533-548. [Crossref]
- Klein D, Patzko A, Schreiber D, van Hauwermeiren A, Baier M, et al. (2015) Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot-Marie-Tooth disease in mice. Brain 138: 3193-3205. [Crossref]
- Antezana M, Sullivan SR, Usui M, Gibran N, Spenny M, et al. (2002) Neutral endopeptidase activity is increased in the skin of subjects with diabetic ulcers. J Invest Dermatol 119: 1400-1404. [Crossref]
- Baron R, Hans G, Dickenson AH (2013) Peripheral input and its importance for central sensitization. Ann Neurol 74: 630-636. [Crossref]
- Fay NS, Larson EC, Jameson JM (2016) Chronic Inflammation and γδ T Cells. Front Immunol 7: 210. [Crossref]
- Mikami N, Fukada S, Yamamoto H, Tsujikawa K (2012) Neuronal derivative mediators that regulate cutaneous inflammations. Crit Rev Immunol 32: 307-320. [Crossref]
- Hilliges M, Wang L, Johansson O (1995) Ultrastructural evidence for nerve fibers within all vital layers of the human epidermis. J Invest Dermatol 104: 134-137. [Crossref]
- Zhao P, Barr TP, Hou Q, Dib-Hajj SD, Black JA, et al. (2008) Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain. Pain 139: 90-105. [Crossref]
- Dussor G, Koerber HR, Oaklander AL, Rice FL, Molliver DC (2009) Nucleotide signaling and cutaneous mechanisms of pain transduction. Brain Res Rev 60: 24-35. [Crossref]
- Cook SP, McCleskey EW (2002) Cell damage excites nociceptors through release of cytosolic ATP. Pain 95: 41-47. [Crossref]
- Shipton EA (2013) Skin matters: identifying pain mechanisms and predicting treatment outcomes. Neurol Res Int 2013: 329364. [Crossref]
- Anand P (1995) Nerve growth factor regulates nociception in human health and disease. Br J Anaesth 75: 201-208. [Crossref]
- Keppel Hesselink JM (2015) The terms 'autacoid', 'hormone' and 'chalone' and how they have shifted with time. Auton Autacoid Pharmacol 35: 51-58. [Crossref]
- Keppel Hesselink JM (2013) Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-alpha agonist and effective nutraceutical. J Pain Res 6: 625-634. [Crossref]
- Keppel Hesselink JM, Kopsky DJ (2015) Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome. J Pain Res 8: 729-734. [Crossref]
- Keppel Hesselink JM (2013) Professor Rita Levi-Montalcini on nerve growth factor, mast cells and palmitoylethanolamide, an endogenous anti-inflammatory and analgesic compound. J Pain Relief 2: 114.
- Kopsky DJ, Keppel Hesselink JM (2013) Neuropathic pain as a result of acromegaly, treated with topical baclofen cream. J Pain Symptom Manage 46: e4-5. [Crossref]
- Keppel Hesselink JM, Kopsky DJ, Sajben NL (2014) Vulvodynia and proctodynia treated with topical baclofen 5 % and palmitoylethanolamide. Arch Gynecol Obstet 290: 389-393. [Crossref]
- Kopsky DJ, Keppel Hesselink JM (2011) Multimodal stepped care approach involving topical analgesics for severe intractable neuropathic pain in CRPS Type 1: A case report. Case Rep Med 2011: 319750. [Crossref]
- Kopsky DJ, Keppel Hesselink JM (2010) A new combination cream for the treatment of severe neuropathic pain. J Pain Symptom Manage 39: e9-9e10. [Crossref]