Pain Management in Dermatology

Pain is a frequently encountered problem in dermatology. A large number of dermatoses are responsible for pain. For example, more than half of patients suffering from psoriasis or atopic dermatitis (AD) report pain, often with a neuropathic component [1]. Zoster and postherpetic neuralgia (PHN) are also responsible for significant, chronic, neuropathic pain. Chronic lower limb ulcers are responsible for chronic pain, and there appears to be a neuropathic component [2]. In addition, ulcer care is also painful for the patient [3]. Many dermatological procedures are responsible for acute pain which may limit their use, such as skin surgery, dynamic phototherapy, botulinum toxin or filler injections for aesthetic purposes, or botulinum toxin injections at the palmoplantar region to reduce hyperhidrosis. In this context, it is mainly a question of preventing the occurrence of pain. The aim of this review was to explore the treatments available to manage pain in dermatology in different circumstances, with an emphasis on pharmacological and non-pharmacological interventions specifically studied in dermatology.

A PubMed, Cochrane, and Google Scholar search was conducted for papers published since January 1, 2000, using the following terms: “pain management AND dermatology.” Then, additional searches were performed on drug interventions and non-drug alternatives for analgesic treatment (such as hypnosis, virtual reality, musical interventions, transcutaneous electrical nerve stimulation) for each circumstance studied. Articles in languages other than English or French were excluded. The articles were selected first based on the title and then on the abstract, and the full text of all potentially relevant articles was retrieved for detailed evaluation. Reference citations within identified articles were also examined to ensure that all relevant evidence was retrieved.

There is still a lack of evidence to confirm pain relief from many AD treatments [4]. Most of them have been shown to be effective in treating pruritus; however, most treatments for AD have been poorly studied for their effect on skin pain [4, 5]. But pain seems to be a distinct symptom from itch in AD which significantly impairs quality of life [6, 7].

Clinical application of common analgesics treatments in AD patients has not yet been reported [4]. A Danish study showed that analgesic consumption was not increased in AD patients compared to the general population. Among patients with severe AD, there was a slightly higher consumption of pregabalin/gabapentin but not significantly. This supports that skin pain is probably reduced by adequate AD therapy [8].

A position paper proposed a treatment algorithm for the management of itch and skin pain in AD patients. It is based initially on the specific treatments for AD and in the event of persistent pain on adding a specific pain treatment (common analgesics, gabapentinoids, antidepressants, anti-JAK, anti-PDE4, opioids) [5].

Recently, Silverberg et al. [6] showed, through a post hoc analysis of 2,632 patients, that dupilumab with or without topical steroids, alleviates pain/discomfort in a significantly higher proportion of patients relative to placebo or topical steroids. The mechanism by which dupilumab reduces pain in AD is unclear, but dupilumab has been shown to significantly alleviate inflammatory skin lesions. Reducing inflammation can lead to lower levels of inflammatory mediators of pain, and skin integrity may protect sensory nerve endings against external nociceptive stimuli [6].

Thyssen et al. [9] found that baricitinib allowed rapid enhancement in patient-reported skin pain in AD from the first day after first dose administration. This can be explained because JAK inhibitors modulate gene expression to restore normal cytokine profiles, which leads to improve the neuroimmune communication that reduces pain [10].

It has been shown that about half of the patients with psoriasis report skin pain [1], and this is not directly correlated with the severity of the Psoriasis Area Severity Index (PASI) score [11]. Improvement in psoriasis lesions predicts the reduction in the intensity of skin pain [11]. Therefore, treatment of the underlying cause permits pain management but treating psoriatic lesions alone may be insufficient for short-term pain. In the absence of official guidelines, relief options for acute pain may include mild analgesics, such as acetaminophen, NSAIDs, and mild opiates [12], but they have not been evaluated specifically in psoriasis.

The efficacy of specific psoriasis treatments is assessed via various scores, notably the PASI and Physician Global Assessment (PGA) score, but this does not always capture skin pain, so further trials are being conducted to assess the impact of these treatments on skin pain. A prospective study shows that calcipotriol plus betamethasone dipropionate in aerosol foam formulation not only improves skin lesions but also improves skin pain from the first week of application [13].

In two phase 3 trials, apremilast allowed an 80% improvement in skin discomfort and pain at week 2 [14]. Some biologic therapies have been studied for their effects on skin pain. A report demonstrates a significant improvement in pain for 70% of patients (n = 820) after 2 weeks of treatment with secukinumab in patients with moderate-to-severe plaque psoriasis, compared to 48% of patients on etanercept and 6% on placebo [15]. A study about three 12-week phase 3 clinical trials shows that ixekizumab has statistically significant improvements in skin compared with etanercept and placebo [16]. Risankizumab permits significantly lower Psoriasis Symptom Scale (PSS) score, which includes an item on pain intensity, compared with those in the placebo group at week 4 [17].

Pain in pemphigus is poorly studied. Tamasi et al. show that half of patients report skin pain [18] (N = 109). There are few studies that specifically address pain management in patients with pemphigus [19, 20]. In the absence of specific analgesic management recommendations for pemphigus, the rules laid down by the WHO apply, i.e., use an analgesic adapted to the intensity of the pain [21]. In cases of moderate to severe pain (intensity > or = 4/10 on a numerical scale of 0–10), opioids should be started immediately [22]. Fentanyl has the added advantage of being rapidly absorbed across the mucosa and having a short onset and duration of analgesia [23]. Most recently, the use of low-level laser therapy on pemphigus-induced erosions resulted in a decrease in erosion size and an improvement in pain [24]. Sleep and prevention of insomnia have also been shown to improve wound healing and pain and decrease stress-induced cytokine release [24]. A case report shows the efficacy of topical ketamine in the treatment of pain in oral pemphigus, independent of lesion healing [25]. A clinical case report was done on the efficacy of gabapentin in the treatment of pain in fentanyl-resistant severe pemphigus vulgaris [26].

The management recommendations are similar to those for burn patients [27], as those patients are indeed often admitted to the burn unit [28]. Frequent pain assessment is necessary [27, 29]. Recommendations for supportive care have been proposed by the Society of Dermatology Hospitalists in 2020 [30]. It is proposed that oral synthetic opiates control moderate pain, and morphine or fentanyl are administered intravenously for severe pain [30, 31]. It is also possible to use low-dose ketamine [30]. Gabapentin and pregabalin are useful for neuropathic pain [30]. For oral involvement, mouthwashes with lidocaine are recommended for analgesic purposes, as well as topical coating agents, such as hydroxypropyl methylcellulose film-forming agents [30]. A urinary catheter is inserted to decrease pain during urination [30]. By analogy to the management of burn patients, non-drug analgesic methods can be proposed such as hypnosis, relaxation, distraction media in combination with medicinal methods [32]. Adding an anxiolytic to local and general analgesic treatments can improve anxiety and the perception of acute pain [29]. The use of non-adherent dressings is recommended [27], and the Society of Dermatology Hospitalists pleads for preserve detached epidermis as a biologic dressing [30].

One of the most painful moments in the acute phase remains mobilisation, bathing [29], and dressing care [32] pain may be controlled by IV opioid analgesics (e.g., fentanyl), IV anaesthetic agents (e.g., propofol, ketamine, dexmedetomidine, lidocaine), oral opioid analgesics (e.g., oxycodone, hydromorphone), oral ketamine, oral clonidine, and inhaled nitrous oxide [29, 32]. For more severe procedural pain, general anaesthesia, deep sedation, or regional anaesthesia could be necessary [32].

In the acute phase, conventional analgesics can be prescribed according to European consensus and follow the three-step WHO pain ladder as based on the severity of pain, and because of the neuropathic component of pain, tricyclic antidepressant or antiepileptic drugs (e.g., gabapentin, pregabalin) may be added [33]. A small study (N = 38) found that lidocaine patch 5% was well tolerated and effective in herpes zoster acute neuralgia with a rapid pain relief and reducing the use of systemic analgesics from the second week and could prevent PHN [34]. It is also effective in PHN [35]. A prospective randomized controlled trial, about 97 patients with acute thoracic herpes zoster, showed that a single intra-cutaneous injection of local anaesthetic (ropivacaine) and steroid (methylprednisolone) resulted in significant lower pain intensity, shorter pain duration, and decreased course of skin eruption [36], but results were not significant for prevention of PHN [36]. Cochrane reviews found that oral aciclovir does not prevent PHN but permits a reduction in the incidence of pain in the short term [37], and corticosteroids in the acute phase are also ineffective in preventing PHN [38], neither is gabapentin [39]. A Korean meta-analysis found that continuous epidural block, antiviral agents with intra-cutaneous or subcutaneous injection with local anaesthetics and steroid, and paravertebral block combined with antiviral and antiepileptic agents would be effective strategies at the acute phase for preventing PHN [40].

Postherpetic pain is treated as pure neuropathic pain: amitriptyline, pregabalin, and gabapentin have been studied specifically in PHN and provides a good pain relief, with moderate-quality evidence [41‒43]. In contrast, there is little evidence to support the use of nortriptyline and oxcarbazepine in the context of neuropathic pain, especially as these molecules have been poorly studied in PHN [44, 45]. But crossover trial suggests that associate gabapentin and nortriptyline seems to be more efficacious than either drug alone for neuropathic pain including PHN, without increasing side effects [46]. Concerning duloxetine, there is moderate-quality evidence that it is efficacious for treating pain in diabetic peripheral neuropathy, but it was not specifically studied in PHN [47]. High-concentration topical capsaicin (8%) is better than very low concentration in people with PHN and provides a good pain relief for 2–12 weeks after a single application [48]. Small-sample studies provide emerging evidence of possible effectiveness of botulinum toxin in the treatment of PHN because it can inhibit the release of neurotransmitters (glutamate, substance P, and calcitonin gene-related peptide) and permit the relief of neuropathic pain [49, 50]. Data are also emerging on the effectiveness of transcutaneous electrical nerve stimulation (TENS) in the treatment of neuropathic pain, based on the fact that TENS activates nerve fibres and induces the release of the endogenous opioid, the modification of electrical transmission, and the dilation of blood vessels [51]. A randomized trial (N = 20) found a significant decrease in pain scores by using TENS in PHN [52]. However, a Cochrane review is unable to state the effect of TENS for neuropathic pain relief due to the very low quality of evidence [53]. Finally, there is a benefit to vaccination for older adults. Moderate-quality evidence suggests that among people aged 60 years and over, vaccines may reduce the incidence of herpes zoster for at least 3 years after vaccination [54].

The management of pain in genital herpes is poorly studied. Aciclovir and valaciclovir can reduce the duration of symptoms [55]. The 2017 European guidelines suggest the use of lidocaine gel but avoid benzocaine, which has a risk of sensitisation [56]. A study has shown the analgesic efficacy of barrier genital gel for controlling pain and time to heal was significantly shorter [57].

Most patients with chronic lower limb ulcers have permanent pain, which worsens during treatment. Pain increases cortisol levels, the heart rate, and the blood pressure, which can hinder healing [58]. Neuropathic pain is frequently present [2]. Depending on the type of pain, an appropriate analgesic should be selected [59]: conventional analgesic and/or antiepileptic drugs (pregabalin, gabapentin), tricyclic antidepressants, or nonselective serotonin reuptake inhibitors for neuropathic pain. But to our knowledge, there are no specific studies on their effectiveness in the management of ulcer pain. EMLA cream can be applied before detersion or lidocaine spray, which has an almost immediate but superficial effect [58]. During the treatment, a nitrogen monoxide-oxygen mixture (MEOPA^®) can be inhaled, which has an analgesic, sedative, and amnesiac effect allowing a less traumatic memory of the act. However, it is difficult to use in outpatient settings [60]. Furthermore, a study showed that the application of EMLA^® cream was more effective than nitrous oxide during ulcer debridement [61]. Anxiety can generate muscle contractions, increase the heart rate, and increase the pain intensity [59]. The use of benzodiazepines before care is possible, as well as the use of music and, if the practitioner is trained, hypno-analgesia, but no specific study seems to exist. Self-adhesive edges and dressings that adhere should be avoided [60]. Ibuprofen-based dressings have an analgesic effect, provided that the ulcer is exudative [62]. In addition, when cleaning with saline, the ulcer should be dabbed, not rubbed [60]. Finally, several articles reported the analgesic efficacy of sevoflurane for topical use in venous or arterial ulcers and pressure sores. This molecule is used in general anaesthesia. There are no large-scale studies, just case reports and small prospective series. Its tolerance is good, with no systemic adverse effects, and only a few local adverse effects: erythema and a sensation of heat, burning, or pruritus [63, 64].

Recurrent aphthous stomatitis is a common cause of pain. Regardless of cause, several symptomatic topical treatments are possible: corticosteroids, cyclosporine, retinoids, antimicrobials, anaesthetics [65]. Small lesions are often adequately controlled with use of a protective emollient such as Zilactin or orabase, used alone or with a topical anaesthetic [66] for instance with lidocaine or benzocaine [67]. In patients with more frequent or severe disease, the use of a topical glucocorticoid is an effective therapy to decrease the size and healing time of the ulcers [66]. Another approach is the prevention of ulcer formation, especially for major ulcer forms. Colchicine is effective for this indication [66]. In the most severe cases, the use of thalidomide remains possible [66]. Dapsone, azathioprine, and etanercept are also effective to manage major RAS [66]. Table 1 summarises the general analgesic recommendations for neuropathic or nociceptive pain-inducing pathologies.

During surgical interventions on the skin under local anaesthesia, the pain felt by the patients is moderate and corresponds to the level of anaesthesia infiltration [68‒72]. Post-operative pain is maximal on the same day [73]. Preoperative anxiety is predictive of greater post-operative pain and even chronic pain [69, 74‒76]. The first approach is to prepare the patient well for the surgery, with clear explanations of the procedure and the expected benefits. For the most anxious patients, premedication with benzodiazepines can be considered [77] (midazolam has been successfully studied in healthy patients undergoing Mohs surgery [78]). A dose of analgesic before or just after the procedure reduces pain during the first 24 h (acetaminophen, ibuprofen, diclofenac, celecoxib) [77]. For post-operative pain, ice can be applied to the surgical site [72, 77], and the patient can take acetaminophen or NSAIDs as a second-line treatment [79, 80]. Opiates are rarely needed, so it is not advisable to prescribe them routinely, especially as there is a risk of misuse and abuse [70]. Concerning the pain experienced during the injection of anaesthetics, it is particularly intense in the face, nose, extremities, axillary hollow, and perineum [70, 73, 75]. The application of a topical anaesthetic such as lidocaine/prilocaine cream (EMLA^®) before could be effective in reducing the pain during anaesthetics injection [81], notably in the perineum [71]. However, a randomized control trial about open trigger digit did not show any statistical difference in pain between the EMLA and placebo group during the needle insertion [82], and another trial found that EMLA cream prior to digital nerve block of the big toe had no clinical benefit [83]. In all cases, the injection technique also influences the pain felt and can be modulated. It is less painful to inject at a 90° angle and to inject slowly [84, 85]. Applying cold before infiltration, for example, cold air [86] or ice [87], or using a mechano-anaesthesia technique like vibration device [76, 87‒89] is effective in reducing pain. A study shows that nitrogen monoxide-oxygen mixture (MEOPA) was more effective in reducing anaesthesia-induced pain during Mohs surgery compared to ice and vibration [90]. The use of lidocaine buffered with sodium bicarbonate in 3:1 ratio, producing a less acidic pH, significantly reduces pain. Sodium bicarbonate is more effective than sodium chloride as a diluent because it will release CO₂ at the injection site with a direct local anaesthetic effect [85, 91, 92].

Attention distraction techniques can be associated. Two systematic reviews on the use of musical interventions in surgery found that music reduced pain and anxiety [93, 94]. The type of music and duration did not seem to influence the outcome, but a tempo of 60–80 beats per minute, an absence of speech, low tones, strings, and a maximum volume of 60 dB were the most effective [93]. In dermatology, the results are contradictory; a study shows that a classical music intervention significantly reduced patient pain and anxiety associated with local anaesthesia during non-Mohs dermatologic procedures [95]. But a prospective study about patient undergoing skin surgery showed no significant relief of pain and anxiety when listening to music. However, the anxiety of the operator decreased significantly, with possible benefits for the surgical result [96]. Anxiety may mediate the relationship between musical interventions and pain experience. In general, the risk of bias in these studies was moderate to severe and limits the interpretation of the results, explaining that they are contradictory from one study to another. There is little evidence to suggest a benefit of listening music during skin surgery [97], but its implementation is easy and inexpensive with a possible beneficial effect and no notable adverse events [84].

Technologies that modify reality by enhancing or modifying a real or artificially created computer environment could be beneficial to reduce pain and anxiety during skin surgery [98]. Few studies specifically concern cutaneous surgery. A prospective study on 100 patients showed that virtual reality was effective in reducing anxiety during Mohs surgery but did not significantly reduce pain [99]. Until now, there has been no codified use of this technique.

Hypnosis is increasingly used and studied in the medical field for pain relief [100]. A randomized controlled trial showed no analgesic effect of hypnosis but a reduction in anxiety during dermatologic surgery [101]. Conversational hypnosis is a possible approach and was effective in reducing perioperative anxiety in a study in a gynaecological surgery department. However, the caregiver must be trained [102]. There are no trials yet in dermatology with this technique. Conversational anxiolysis, on the other hand, is used intuitively by practitioners [68].

Pain during photodynamic therapy (PDT) is the main limiting adverse effect of the use of this technique [103]. Topical anaesthetics are not effective in reducing pain [104]. Scalp nerve blocks provide an effective method for pain management during PDT for patients with extensive actinic keratoses [105, 106]. Another study showed that nerve block is superior to cold air [107]. Another controlled trial showed that scalp nerve blocks are more effective than intravenous analgesia (piritramide and metamizole) or cold air analgesia; and no significant difference in terms of pain relief was found between cold air alone and cold air combined with intravenous analgesic [108]. Cooling methods permit significant reduction in pain, but minor [109, 110] and there is no difference between cold-water spray and cool pack [109]. Pause illumination was more effective [109, 111]. Nitrous oxide/oxygen mixture is a very effective and well-tolerated method for achieving significant pain reduction during PDT [112]. Hypnosis is poorly studied in PDT; in a series of 12 patients undergoing PDT, hypno-analgesia was effective for 8 [113]. TENS permitted reduction of pain during procedure for AK on the scalp in a study. The electrodes were placed on the shoulder [114]. Finally, there is less discomfort with daylight PDT [115].

The injections for aesthetic purposes in the face are painful. Several analgesic techniques have been tested, often on small patient samples. The application of a system delivering a vibration during the injection seems to significantly reduce the pain during the injection of botulinum toxin [116, 117] or dermal filler [118] in the face. Several cold anaesthetic techniques have been studied with encouraging results. The application of fluoroethane- or ethyl chloride-based cooling spray significantly reduced pain during botulinum toxin or dermal filler injections in the face [119]. It also appeared to be effective in reducing discomfort during palmar and plantar botulinum toxin injections for hyperhidrosis [120]. It was compared to ice packs during palmar neurotoxin injections for hyperhidrosis and was superior in terms of pain reduction [121]. Similarly, the ethyl chloride spray was more effective than EMLA cream in reducing pain during neurotoxin injections in the forehead [122]. Another series of patients receiving botulinum toxin injections for palmar hyperhidrosis showed the superiority of ice packs over EMLA cream in reducing pain [123]. In contrast, Elibol et al. [124] found that both EMLA cream and ice gel pack significantly reduce pain when injecting periocular neurotoxin, but there was no difference between ice and EMLA. Applying a spot cooling device reduces patient discomfort in patient undergoing dermal filler procedure [125]. Finally, hyaluronic acid filler is now often prepared with lidocaine, which significantly reduces the sensation of pain immediately after the procedure [126]. An open-label study found that nitrous oxide/oxygen mixture significantly decreases VAS pain score during botulinum toxin injection in the axillae and palms [127]. Finally, hypnosis seems to be an effective tool to reduce pain related to palmar botulinum toxin injections [128]. General analgesic rules for procedural pain are given in Table 1.

We propose a practical summary in Table 1. There are a lot of data emerging on the painful nature of AD and psoriasis. However, the effectiveness of the treatments for these diseases is evaluated based on the relief of pruritus but still little on pain relief, even though additional trials are carried out in this sense. As for general pain treatments, the rules of which are laid down by the WHO in the context of cancer-related pain, they have not been studied specifically in skin diseases, except in PHN. With regard to dermatological procedures, analgesic drug management is rather well studied in skin surgery. The data are less robust for PDT or botulinum toxin injections. In addition, there are new data on non-drug analgesic methods such as hypnosis, TENS, virtual reality, or musical interventions.

Analgesic methods are numerous but still too little studied specifically in dermatology.

Laurent Misery: Galderma, Lilly, and Pfizer – speaker, investigator, and consultant, and Pierre Fabre – speaker and consultant. Mathilde Hayoun: no conflict of interest to declare.

No funding was received for this study.

Laurent Misery: conceived and designed the review, critical review of the intellectual content of the work, final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Mathilde Hayoun: corresponding author, conceived and designed the review, collected the data, wrote the paper, final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.