Nociceptive pain is the most frequent type of pain in individuals with SCI [7]. It is possible to differentiate between the types of pain by determining pain quality/characteristic, distribution, clinical course, and responsiveness to any therapeutic approach. Nociceptive pain may respond well to a variety of different therapy strategies including surgical/interventional, pharmacological, and physical therapy. Its etiology can be assigned to three different subtypes:

At-level neuropathic pain is located anywhere within the dermatome of the neurological level of injury and/or three dermatomes below this level [23]. Pain caused by damage to the cauda equina is always classified as at-level pain, also in cases where it extends more than three dermatomes below the neurological level. Below-level neuropathic pain is located in the region more than three dermatomes below the neurological level of injury, but may extend to the at-level area. Neuropathic pain is often described as shooting, pricking, squeezing, or burning. Allodynia – most often to touch or cold stimuli and hyperalgesia to pinprick or thermal stimuli – may be present.

Neuropathic pain following SCI may occur immediately at the time of injury but may also have a delayed onset up to several months. At-level neuropathic pain often has an earlier onset than below-level pain [7]. Neuropathic pain may diminish or resolve during the first year [34], but often becomes chronic, and patients who experience neuropathic pain at 6 months are likely to have neuropathic pain with the same intensity 5 years after their SCI [7]. Paresthesia, which is described as abnormal sensations that are not painful or unpleasant, and dysesthesia, which is described as unpleasant abnormal sensations, are often present following SCI, e.g., an ongoing tight sensation or a tingling sensation occurring either spontaneously or evoked by, e.g., touching the area.

Recent studies have found that early sensory hypersensitivity predicts later development of central pain [8, 35]. In one study in incomplete SCI, sensory hypersensitivity (mechanical allodynia and temporal summation of pain) and hyperpathia in the first months after SCI preceded ongoing below-level SCI pain [35], whereas in another study, early (1 month) sensory hypersensitivity (particularly cold-evoked dysesthesia) was a predictor of the development of below-level SCI pain [8]. Interestingly, sensory hypersensitivity did not predict at-level SCI pain, supporting that these two pain types are two different pain phenomena, presumably with different underlying mechanisms [7].

The mechanisms involved in SCI neuropathic pain are multiple and only incompletely understood. A SCI allegedly causes irreversible functional changes in the vicinity of the lesion site. These include neuronal hyperexcitability, impaired modulation from interrupted supraspinal control, and destroyed spinal circuitries. Insights from animal models indicate the presence of regenerative processes that are characterized by structural adaptions (e.g., rewiring of axonal connections) and changes in signal transmission on cellular level [36–39]. Besides its assumed linkage to spontaneous recovery after SCI, this so-called plasticity may also cause fundamental changes in the transmission of pain signals and therefore lead to detrimental effects with neuropathic pain as a possible consequence. Such neuronal changes include an increased sensitivity to sensory stimuli and a disturbed balance between excitation and inhibition. Ongoing spontaneous activity in central pain pathways rostral to the site of injury are thought to cause spontaneous pain, and neuronal hyperexcitability may cause increased pain to painful stimuli, decreased pain thresholds, aftersensations, and spread of pain. Central sensitization is defined as increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input [32]. Several molecular changes seem to be involved, including changes in the N-methyl-D-aspartate (NMDA) and other glutamate receptors [40], sodium, calcium, and potassium channel expression [41, 42], glia cell activation and release of pro-inflammatory cytokines [41, 43–45], degeneration of inhibitory dorsal horn interneurons containing γ-aminobutyric acid (GABA) [46], and loss of inhibition from descending pathways, dependent on monoamines such as noradrenaline, serotonin (5-HT), and dopamine. Significant structural changes lead to reorganization, such as intraspinal sprouting of calcitonin gene-related peptides and substance P containing fine primary afferents and Rac1-regulated remodeling of dendritic spines on dorsal horn neurons [47–50].

There is evidence from human studies to support that the changes occurring at the injury site of the spinal cord are important for both at- and below-level pain. In some cases, spinal transection and dorsal root entry zone (DREZ) lesions may relieve both at- and below-level pain, suggesting that the area around the spinal lesion acts as a pain generator. However, these procedures also carry the risk of development of central pain [51–53]. It has also been shown that sensory hypersensitivity at the level of injury and that the percentage of rostral gray matter lesions are highest in patients with below-level pain [54, 55]. It is hypothesized that ectopic activity arising at the rostral part, transmitted via multisynaptic propriospinal pathways, may also play a role in SCI pain [54]. Activity in residual spinothalamic tract neurons may additionally contribute to the generation of pain after SCI [56]. In addition to changes in neuronal excitability at the spinal cord level, changes can be demonstrated in different brain areas following SCI, e.g., the thalamus [57, 58], anterior cingulate cortex, right dorsolateral prefrontal cortex [59], and the somatosensory S1 cortex [60]. Furthermore, pain may be associated with a specific electroencephalography (EEG) signature with increased power in the theta and alpha bands in the relaxed state [61]. The specific role of these changes in generation or modulation of pain is unknown. In summary, neuronal hyperexcitability at the level of injury, spared polysynaptic pathways, and partially spared spinothalamic tract neurons, together with deafferentation resulting in abnormal neuronal brain activity, are possible mechanisms that are involved in the development and manifestation of SCI neuropathic pain.

Experimental models are crucial for improving our understanding of molecular SCI pain mechanisms and for testing new drugs. Assessing pain-like behavior in animals is, however, challenging [62], particularly after central nervous system lesions [63, 64]. Due to the development of the spastic syndrome, the specific assessment of pain-like behavior in rats with SCI cannot rely on the evaluation of simple reflexes and withdrawal thresholds but requires tests that involve brainstem-dependent responses such as licking, guarding, and escape or more complex, cerebrally mediated behaviors.

Nociceptive pain is considered to be amenable to certain therapeutic strategies, including interventional but also nonsurgical and instrument-based therapies. The level of evidence for these approaches is varying to a large degree and sometimes it is very low.

Whenever possible, therapy should primarily focus on the elimination of the underlying causes, such as administration of laxatives, fracture treatment, wound care, or reduced stress on overused joints [85]. Surgical interventions addressing arthrosis or ankylosis of the shoulder joint in patients with paraplegia are subject to controversial discussions. Even though reported to be effective following a careful risk-benefit analysis and in consideration of the time and costs for the post-interventional rehabilitation period, such complex interventions should only be considered with caution in SCI patients due to a high risk for recurrent articular complaints [86–89].

The second mainstay of routinely applied therapy strategies is represented by mostly temporary pharmacological treatment. This approach includes nonsteroidal anti-inflammatory drugs (NSAID), such as ibuprofen or diclofenac, as well as other non-opioid pain drugs, such as metamizole [85]. In markedly severe cases, opioids could also be an option for symptomatic pain therapy. The “WHO Treatment Guidelines on chronic nonmalignant pain in adults” are currently being developed, but not yet published [90]. Until then, the “WHO’s cancer pain ladder for adults” may be used as orientation guideline, since it is a widespread clinical tool that is also commonly used in nociceptive pain management [91, 92]. However, there are still no evidence-based treatment recommendations based on randomized clinical trials in SCI, as well as in general pain therapy of adults. Individualized pain management concepts, based on the underlying pathology, should be considered in given cases [92].

Both aforementioned approaches should always be embedded in a multimodal therapy setting that comprehensively addresses the patient’s complaints. Such supportive therapies primarily involve physical therapy, including general or symptom-oriented exercise programs [93–98]. Numerous further non-pharmacological and nonsurgical therapy approaches have already been tested in various studies and/or trials. Among them, acupuncture was found to have beneficial effects on musculoskeletal pain in SCI [99, 100]. However, it does not seem to be superior to the control interventions consisting of physical activity and sham acupuncture, respectively. Instrument-based therapies such as transcranial electrical stimulation (TCES) or transcutaneous electrical nerve stimulation (TENS) have also been tested, especially for their effect on general pain relief, which also includes musculoskeletal pain intensity. Thus, TCES and TENS admittedly delivered indications for efficacy in this context, yet existing clinical trials are few, methodically heterogeneous or not focused on SCI pain [101–108]. Furthermore, low or insufficient evidence of efficacy in SCI-related musculoskeletal pain has yet to be stated for conservative methods, such as massage, heat therapy, or behavioral management (e.g., hypnosis or cognitive behavioral therapy) [81, 109–112]. In consequence, if and to what extent such a therapeutical regimen should be added has to be decided on an individual basis.

If possible, the underlying causes should be treated, but often symptomatic treatment is the only option. So far, no treatment has proven successful in preventing neuropathic SCI pain. It is important to exclude other causes of pain such as musculoskeletal pain and to consider factors that may aggravate neuropathic pain such as pressure sores, spasticity, or bladder infection. It is also important to evaluate the impact of pain on daily life, sleep and mood, psychological factors, and risk of suicidal ideation.