FormalPara Key Points

We present a systematic review that comprehensively evaluates the analgesic effects of calcitonin for patients with phantom limb pain (PLP).

The available evidence supported the use of calcitonin as either monotherapy or adjuvant therapy in the treatment of PLP during the acute phase, while the evidence surrounding calcitonin treatment in chronic PLP is heterogeneous.

1 Introduction

The first descriptions of phantom sensations, including phantom limb pain (PLP), are attributed to the French military surgeon Ambroise Paré, who described the phenomenon following limb amputation in 1551 [1]. PLP refers to pain perceived in a part of the body removed by amputation or trauma (or, less commonly, in a limb that did not form due to a congenital defect), and is distinct from pain in the region of the residual limb or ‘amputation stump’ itself [2]. Despite the longstanding recognition of PLP, its precise causes remain unknown; however, both central and peripheral nervous system factors in the nerve pathway severed by amputation have been implicated in its development [3, 4]. Etiological theories of PLP have been previously and thoroughly reviewed elsewhere [4, 5].

Despite great progress, especially in the field of regional anesthesia and physiotherapy, the incidence of PLP following surgical or traumatic amputations is still very high, with between 27 and 86% of patients experiencing this phenomenon after the loss of a limb [6, 7]. Patients typically report symptomatic onset days to weeks after the amputation, although we have previously reported a case wherein an individual developed PLP immediately after surgery [8]. The discomfort associated with PLP is often severe and is a significant source of post-amputation morbidity. For example, a cross-sectional study of adult patients with PLP following lower limb amputation reported an average pain intensity of 50–79 on the 0–100 visual analog scale (VAS) at 3 months postoperatively [9]. However, PLP is often experienced in discrete episodes lasting less than an hour, and approximately half of patients with PLP experience one or fewer episodes of pain per week [10]. Only 13–16% of patients with PLP experience chronic pain, although the mean duration of PLP for these individuals is 26 years [11, 12]. Furthermore, persistent symptoms have been described as long as 38 years after amputation [13].

There is a paucity of randomized controlled trials for either pharmacological or non-pharmacological treatments of PLP, and available studies are highly heterogeneous with regard to indications (e.g. trauma, vascular disease), types of surgery, perioperative anesthetic care (e.g., regional anesthesia techniques), specific analgesic interventions, and outcomes. Consequently, current recommendations mainly underscore meticulous surgical technique and judicious perioperative analgesia adapted to individual patients as the mainstays of PLP prevention [14]. The American Pain Society’s Guidelines on the Management of Postoperative Pain strongly recommend the incorporation of pregabalin or gabapentin into a multimodal perioperative analgesic regimen for any major surgery where patients are likely to suffer severe perioperative pain, and offer a weak recommendation for intravenous ketamine [15]. Similarly, epidural administration of local anesthetics and opioids appears to decrease the likelihood of developing PLP after lower limb amputation [16]. In addition to aiding with analgesia and possibly PLP prevention, these perioperative interventions have an opioid-sparing benefit in the postoperative period [17,18,19]. However, while these are important considerations for mitigating the development and severity of PLP, the condition is unfortunately unpreventable with current therapies.

For patients experiencing PLP, pharmacological treatment options include morphine and gabapentin (although each bears a significant adverse effect profile), as well as ketamine with the caveat that its analgesic effects for PLP do not extend beyond the duration of application [5]. Local therapy with 8% capsaicin patches has been promising, although with a modest effect size, and studies on botulinum toxin and oral N-methyl-d-aspartate (NMDA) receptor antagonists have been predominately inconclusive [20, 21]. For example, short-term analgesia has been reported with dextromethorphan, while memantine and amitriptyline have been shown to be ineffective for PLP [14]. Presently, only case reports describe the use of serotonin and norepinephrine reuptake inhibitors (SNRIs) in the treatment of PLP [22, 23].

Numerous non-pharmacological options have also been applied in the treatment of PLP, although with mixed efficacy. These include the stimulation of severed nerve fibers within the amputation stump using electrodes or cotton swabs, which positively influences both cortical remapping and the intensity of patients’ experience of PLP [14]. In mirror therapy, patients experience visual reactivation of a lost limb by viewing mirrored reflections of the remaining contralateral limb, and this has been shown to reduce the risk of developing PLP [24]. Cognitive behavioral therapy is also widely considered to be beneficial, however scientific evidence is lacking [25]. Newer treatment modalities with augmented and virtual reality technology are currently in development, and it is too early to draw conclusions about their efficacy for PLP [26]. Similarly, neuromodulation and neuroprosthetic approaches have been described for PLP but are not yet widely available [27]. Therefore, despite the high incidence and significant burden of morbidity associated with PLP after amputation, effective therapies directed at restoring patients’ quality of life through adequate analgesia are currently lacking [14].

There has been a growing interest in the analgesic effects of calcitonin, a polypeptide hormone consisting of 32 amino acids, since its use was first demonstrated in rabbits half a century ago [28]. Recent clinical studies have supported the use of calcitonin as a novel standalone or adjunct analgesic for patients with adhesive capsulitis of the shoulder (‘frozen shoulder’), non-specific lumbar back pain, diabetes-associated neuropathic pain, migraine headaches, and postoperative pain [29, 30]. Calcitonin has also been applied in several studies to successfully relieve acute pain following osteoporotic fractures [31,32,33]. Similarly, a Cochrane meta-analysis reported low-grade evidence that calcitonin is superior to placebo preparations with respect to analgesic efficacy for the management of complex regional pain syndrome (CRPS) [34]. Another meta-analysis suggested that calcitonin is most effective among patients with chronic CRPS lasting longer than 12 months, but its chronic use was associated with an increased oncological risk and therefore the authors recommended a maximum therapeutic course of 6 weeks [35]. Clinical studies classically administer xenogenic calcitonin derived from the ultimobranchial glands of salmon, as it is both more potent and more stable than the human homolog [36].

Given calcitonin’s previously established efficacy for pain relief, this systematic review aimed to comprehensively evaluate the evidence surrounding its analgesic effects for patients with PLP.

2 Methods

This review was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [37]. A reporting checklist is provided in Appendix I. The protocol for this study was registered in the Open Science Framework database (https://osf.io/3mwu7/) [38].

2.1 Databases and Search Strategy

We searched the MEDLINE, OLDMEDLINE, and PubMed Central databases with the queries ‘(calcitonin) AND (phantom limb pain)’, ‘(calcitonin) AND (phantom pain)’, ‘((calcitonin) AND (phantom limb pain)) NOT CGRP’, and ‘((calcitonin) AND (phantom pain)) NOT CGRP’. Additionally, Google Scholar was searched manually with the query ‘calcitonin phantom limb pain’; no additional filters were set. All four databases were searched from inception until 1 December 2022.

Citations resulting from the searches were deduplicated and their titles and abstracts were screened for inclusion or exclusion by two authors independently. The full texts of all potentially relevant articles were subjected to additional screening, again by two independent authors in parallel. Conflicts were resolved by a third author. The reference lists of the included studies and relevant review articles were used to perform a backwards search for further studies not identified in the primary search.

2.2 Inclusion Criteria

The literature search for this review sought clinical trials primarily focused on ascertaining the effectiveness of calcitonin administration, in any form and dose, for the treatment of PLP. Prospective studies examining the effect of calcitonin on the severity of PLP in human patients, alone or in combination with other agents, were considered for inclusion. Articles that did not present original data (e.g., reviews) were excluded. There were no exclusions on the basis of geography or language.

2.3 Data Extraction and Analysis

Data pertaining to demographic characteristics, calcitonin treatment regimens, pain intensity and duration (using studies’ original pain scales for measures of effect), and analgesic requirements were extracted from articles meeting the inclusion criteria. Included reports were grouped by study design in the narrative synthesis, and quantitative data were tabulated using descriptive statistics. The methodological quality of each included study was assessed using the Downs and Black checklist, with overall scores of 26–28 corresponding to high quality, 20–25 corresponding to moderate quality, and < 20 corresponding to low quality [39], and subjected to a Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment of effect certainty and risk of bias [40]. Randomized controlled trials underwent an additional assessment of quality using the Jadad scale (rated from 0 to 5) [41].

3 Results

Our search strategy yielded 4108 articles, of which 2296 were excluded as duplicates during prescreening and 1783 were excluded by title/abstract screening. Twenty-nine articles were eligible for full-text screening and of these, six articles were identified as meeting the criteria for inclusion in the narrative synthesis [42,43,44,45,46,47]. A PRISMA flowchart of the screening and selection process is presented in Fig. 1. Eligible articles were grouped by study design into open-label studies (n = 2) [42, 43], prospective observational studies (n = 1) [45], and randomized clinical trials (n = 3) [44, 46, 47].

Fig. 1
figure 1

Flowchart of the systematic review

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Three of the six papers were rated as moderate methodological quality [44, 46, 47], and the remaining three were rated as low methodological quality [42, 43, 45] on the Downs and Black checklist (Table 1). The data extracted from the included studies for analysis are summarized in Table 2.

Table 1 Downs and Black methodological quality checklist for the included articles
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Table 2 Characteristics and outcomes of studies included in the systematic review
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3.1 Open-Label Studies

Mertz was among the first to clinically investigate calcitonin’s effect on PLP [24]. In his 1986 study, Mertz [42] recruited 20 male World War II veterans who had lost one or more of their extremities and subsequently suffered from severe PLP. Fourteen patients were intravenously administered 200 IU of calcitonin diluted in 20 mL of normal saline (0.9% sodium chloride) solution. This treatment group reported a ‘strong decrease in pain symptoms’ during or after the application and remained symptom-free during the observation period [42]. The remaining six patients received placebo treatment and reported a lesser response attributed to the placebo effect: analgesic effects were described as initiating 30–60 min post-injection and were sustained for up to a maximum of 4 h. However, the article is vague by current scientific standards, includes only male subjects, and presents little objective data with which it can be compared with other trials.

In 1987, Kessel and Wörz conducted another open-label study with 10 patients: seven World War II veterans with PLP, two civilian trauma patients, and one patient with peripheral vascular disease [43]. Nine of 10 patients reported a significant reduction in pain following the administration of 100 IU of salmon calcitonin. Inversely, in a second group of participants who suffered from various types of pain other than PLP, calcitonin was ascribed a significant effect in only 1 of the 10 subjects. Interestingly, the responsive patient in this second group experienced stump pain in their left hip and did in fact have a prior history of PLP.

3.2 Prospective Observational Study

In the sole observational study that met the criteria for inclusion, Simanski et al. [45] administered 100–200 IU of salmon calcitonin to four male and four female patients with PLP who had previously experienced inadequate pain relief with other analgesics. Amputations for patients in the cohort were the result of either arterial occlusive disease (5/8) or trauma (3/8), and two participants had concomitant diabetes. After five daily infusions with calcitonin, six of eight participants reported complete resolution of their PLP.

3.3 Randomized Controlled Trials

In 1992, Jaeger and Maier published the first randomized, double-blind, crossover controlled trial with calcitonin as an analgesic for PLP [44]. Twenty-one patients with postoperative PLP of an intensity greater than three (maximum 10) on the numerical rating scale (NRS) were enrolled in the study. Of these, 11 were assigned to an intervention group receiving 200 IU of intravenously administered salmon calcitonin, and the other 10 were assigned to a control group receiving placebo. Four patients in the intervention group reported complete resolution of PLP after a single dose, while the remaining seven required a second infusion after 4–48 h, which, notably, did not lead to any further pain reduction. The 10 participants in the placebo group all required a second infusion within 48 h, which was administered with 200 IU of salmon calcitonin. Across both groups, initial calcitonin treatment resulted in an average pain reduction from 7 to 4 on the NRS. PLP did not recur in 15 of the 21 study participants, and among the patients who did re-experience PLP after calcitonin treatment, the severity of later episodes was reportedly lower.

More recently, Eichenberger et al. [46] reported on the analgesic effects of calcitonin, ketamine, and calcitonin/ketamine in combination for the treatment of chronic PLP. Twenty participants in the study were randomized to receive 200 IU of calcitonin, 0.4 mg/kg ketamine, 200 IU calcitonin with 0.4 mg/kg ketamine, or normal saline placebo in a double-blind crossover regimen. Calcitonin alone was reported to be ineffective, while both ketamine monotherapy and the ketamine/calcitonin combination led to a pain reduction of ≥ 50% in 60% of treated patients, with no statistically significant difference between these latter two groups at early timepoints. However, only patients receiving the combination infusion reported that the reduction in their pain was maintained at 48 h post-injection.

The latest study by Yousef and Aborahma [47] recruited 60 patients with diabetes mellitus scheduled to undergo operative lower limb amputation. The patients were randomized to receive a total of three repeated intra- and postoperative epidural administrations of either 100 IU of calcitonin or placebo, in combination with 10 mL 0.5% bupivacaine and 100 µg fentanyl, until the second postoperative day. PLP intensity was predominately mild in both groups at 1 month following surgery: 29/30 patients in the calcitonin/bupivacaine/fentanyl group and 27/30 in the placebo/bupivacaine/fentanyl group reported mild PLP intensity at this timepoint. However, at the 1-year follow-up, 26/30 patients in the calcitonin/bupivacaine/fentanyl group continued to experience no or mild PLP, while half of the placebo/bupivacaine/fentanyl group continued to experience moderate to severe PLP [47].

4 Discussion

Although relatively few studies report on the effectiveness of calcitonin for PLP, together they suggest an overall treatment benefit. In earlier reports, effect size tended to be estimated as greater, while methodological quality was generally lower. The studies classified as having low methodological quality described predominantly positive results for PLP treatment with calcitonin [42, 43, 45], while the remainder were more measured [44, 47], with only one reporting non-superiority [46].

Notably, the timing of calcitonin administration relative to symptom onset appears to play an important role in its analgesic properties for patients with PLP. For example, two randomized controlled trials showed that calcitonin has an early and often sustained analgesic benefit when administered either shortly after the initial onset of PLP or prior to the amputation [44, 47]. In contrast, studies describing the treatment of PLP with calcitonin at later timepoints produced heterogeneous results [42, 46]; three reported at least partial effectiveness [42, 43, 45], while one randomized controlled trial found no significant benefit of calcitonin as monotherapy or in combination with ketamine [46]. However, it is worth noting that this randomized controlled trial was likely underpowered with a sample size of only 20 patients, of whom 10 received ketamine monotherapy as an independent intervention group. Nonetheless, studies exploring calcitonin as an analgesic for non-PLP patients, such as those with postmenopausal osteoporosis-related back pain [48, 49] or lumbar canal stenosis [29], have been similarly discordant.

Evidence from the reviewed studies, promise the use of calcitonin as an adjunctive pain medication, and warrant further exploration. For instance, the randomized controlled trial by Eichenberger et al. [46] reported that although the immediate analgesic effects of calcitonin and ketamine in combination were not superior to ketamine alone, the combination infusion boasted a superior prolonged analgesic effect at later timepoints (> 48 h) compared with ketamine monotherapy. Yousef and Aborahma [47] corroborated the superior effects of a calcitonin/bupivacaine/fentanyl combination over a placebo/bupivacaine/fentanyl-treated group at a timepoint of 1 year after lower limb amputation.

The effectiveness of calcitonin as an adjunct analgesic has also been described in the treatment of non-PLP pain conditions such as trigeminal neuralgia: when administered as a 50 IU injection in combination with standard lidocaine and methylprednisolone maxillary and mandibular blocks, calcitonin prolongs the duration of analgesia (without significantly impacting its magnitude of effect) compared with normal saline placebo [50]. In another study of 46 patients undergoing surgical management of maxillofacial fractures, calcitonin was not associated with lower subjective pain scores but did reduce the need for other analgesic agents in the postoperative period [51]. Finally, patients undergoing total hip arthroplasty facilitated by epidural anesthesia reported equianalgesic effects with a combined calcitonin/bupivacaine injectate compared with a combined fentanyl/bupivacaine injectate [52].

The relatively benign safety profile of calcitonin makes it an attractive alternative to other short-acting analgesics such as NMDA antagonists (e.g., ketamine), and none of the included studies reported severe adverse effects attributable to calcitonin. Furthermore, calcitonin may play other roles in mediating gastrointestinal, renal, reproductive, and inflammatory functions [53], with possible benefits beyond its proposed analgesic effect. For example, calcitonin is implicated in the mineralization of bone with calcium and phosphate, and is a known inhibitor of osteoclast activity [54]. The wide-ranging activities of calcitonin and its relatively wide therapeutic index make it an attractive possibility for both pain management and a potential opioid-sparing effect for patients with PLP, especially in the context of other medical comorbidities. However, a significant disadvantage of calcitonin is the limited availability of oral formulations, as the requirement for intravenous or epidural administration presents an obstacle to out-of-hospital and long-term use. Furthermore, while oral formulations can be developed (e.g., bound to a caprylic acid derivative), nasal and oral administrations have been associated with an increased risk of cancer [35] and are therefore unlikely to feature in large-scale clinical trials.

4.1 Limitations

Our meta-analysis is clearly limited by the small number of published studies. However, we also found three randomized controlled trials with a low risk of bias, and our statements are based mainly on these studies, which provide a solid foundation.

Another limitation is the heterogeneity of the treatment regimens used. In addition to intravenous application, epidural application was also used. Furthermore, the number of repetitions is highly variable, between 0 and 5 infusions over 10 days after initial treatment.

4.2 Clinical Perspective

Salmon calcitonin, administered intravenously as a 200 IU infusion, is the most frequently used regimen described in the current literature. Our review of calcitonin’s use as an analgesic therapy for patients with PLP supports its application, particularly in the treatment of new-onset pain, in the absence of specific contraindications such as hypocalcemia, hypersensitivity, pregnancy, or lactation. However, the available evidence is limited and suggests that calcitonin monotherapy may not afford complete pain relief for all patients, although it can support the longevity of relief from PLP. If pain persists despite calcitonin therapy, it may be reasonable to repeat such an infusion several times with the expectation of marginal benefit [44].

5 Conclusion

The current evidence supports the use of calcitonin in treating newly developed PLP, although the evidence for calcitonin is conflicting with respect to chronic PLP. Limited therapeutic options for PLP, in combination with its relatively benign safety profile, make further investigation a research priority. Given the paucity of studies examining the analgesic effect of calcitonin and their heterogenous study designs and methodological rigor, future directions of this work will require robust clinical trials of calcitonin monotherapy and/or adjuvant therapy in the treatment of PLP to support its adoption into clinical practice.