Post-surgical Neuropathic Pain

Part
01
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Part
01

Post-Surgical Neuropathic Pain, Part One

We were able to locate some studies giving the prevalence/incidence, demographics, and causality of post-surgical neuropathic pain (PSN). A recent study found the incidence of post-surgical neuropathic pain in Brazil to be 13.4% (female, middle-aged, and ethnically Pardo). Another study found that 25% of Korean patients (mostly male. The mean age at the time of surgery was 36, and the mean age at the time of the questionnaire was 43) who underwent sarcoma surgery reported PSN. A review of the literature indicates that PSN is a result of surgical injury of large peripheral, such as the kind of injury that would result from sarcoma removal.

Methodology

We began our research with an inquiry into medical literature databases (e.g., PubMed, Embase, Cochrane, and EBSCO) and then expanded our search for case reports and literature reviews of post-surgical neuropathic pain. During our search, we found that there had been few studies published that would allow us to provide timely references. Additionally, as reported in one literature review, it is difficult for researchers to properly estimate the prevalence of the condition because of its treatment in the medical literature. We expect that is why our search for global statistics on post-surgical neuropathic pain did not yield extensive results.

Regardless, we expanded our search to journals that deal specifically with pain, anesthesiology, oncology, and surgery. We also looked for any statistics or epidemiological details that could be provided from these sources. Unfortunately, this avenue of inquiry did not produce the information we required. So, our next strategy was to expand our search to articles and publications from news sites such as Forbes, BBC, CNN, The New York Times, and others. Again, this avenue of inquiry yielded no results.

Due to the lack of information on global data, our search looked for epidemiological data from different continents on the previously specified medical sites. We located information for South America, Europe, and Asia. However, some data were outside our time frame for sources. They are included here because in many cases, they were the only data available. While some studies we found did include demographic information, most did not. We were able to find comprehensive demographic statistics from a study done in Kuwait. Unfortunately, the study concerned neuropathic pain in general instead of post-surgical neuropathic pain.

For the sake of accuracy, we expanded our search for demographic data along the same lines and channels as we previously indicated. We began with medical databases. When no information was found, we expanded our search to specific journals. When again no information was forthcoming, we checked any possible media sources. As one final step to find demographic information on post-surgical neuropathic pain, we expanded our search to the sites of hospitals and clinics in the United States. However, we were unable to locate any other relevant data.

Post-Surgical Neuropathic Pain, Part One

In their review of the literature on post-surgical neuropathy (PSN), de Fonseca, Gatto, and Tondato conclude that there have been few studies evaluating the condition. Additionally, even the term “neuropathic pain” is used sparingly, if at all, to refer to pain that occurs after traumatic nerve injury. De Fonseca et al. concluded that, as such, it is difficult to make a proper estimate of the prevalence and incidence of PSN. Though the authors do report there is a worldwide consensus that PSN is a severe problem globally, it is difficult to treat. The data we have collected would appear to support these conclusions.

Epidemiology

According to a recent study performed among chronic pain patients (n=307) at Brazilian hospitals and pain clinics, the incidence of PSN was 13.4%. In de Fonseca et al.’s review of PSN literature, they provide the results of a 21-hospital observational study spread across 11 European countries that evaluated 3,120 surgical patients. According to that study, 35.4% of patients experienced moderate pain, and 57.1% of patients experienced severe pain as a result of PSN. An Italian study of 235 patients found that of those respondents with chronic post-surgical pain, PSN was present in 31.9% of respondents six months after surgery and in 40.3% after 12 months.

In an older, open-label study on PSN using 300 patients and the PainDetect questionnaire, researchers found a 10% point prevalence of PSN. Twenty-six patients were found to have possible PSN; these patients underwent thoracic surgery (5), gynecology/genitourinary surgery (6), bone and soft-tissue surgery (5), breast surgery (5), and head and neck surgery (5). There were five patients that were found to have positive PSN; these patients underwent groin node dissection (2), hemicolectomy (1), open transthoracic oesophagectomy (1), and hemipelvectomy (1).

Another more recent study investigated the associated factors of PSN in patients who underwent surgery for sarcoma of the extremities or pelvis. This study also used the same PainDetect questionnaire used in the previous study. Thirty-six, 25%, patients (out of a total of 144) were diagnosed with PSN. Additionally, the study’s authors found that patients with PSN were more likely to have undergone pelvic surgery (P=.002) and multiple surgeries (P=.014).

In their review of the literature, de Fonseca et al. also report that the estimated incidence of chronic post-surgical pain varies on the type of surgery and technique used. While the incidence of chronic post-surgical pain is experienced by 10%-50% of patients after classic surgeries (with that pain being severe in 5%-10% of cases), the incidence of PSN is 6%-60% depending on surgery type. However, an older study by Borsook et al. places the incidence as 10%-40%. De Fonseca et al.’s review of 281 studies investigating persistent post-surgical pain suggests that the prevalence of probable or permanent NP was high in patients with persistent pain after thoracotomies (66%), mastectomy (68%), groin hernia repair (31%), and hip and knee arthroplasty (6%).

Demographic Statistics

Because these studies were carried out across South America, Europe, and Asia, there is some variation in the demographics among the respondents. In the Brazilian study of neuropathic pain, patients were mostly female (80%), middle-aged (mean age=52.5, SD=13.9) and ethnically Pardo (44.3%). In the study on PSN and sarcoma surgery, the mean age at the time of surgery was 36, while the mean age at the time of the questionnaire was 43. By gender, the majority of the respondents (54%) were male. The sarcoma study does not report the ethnicity of the patients, but it was administered in South Korea. Given that the researchers make no mention of it in their report, likely all respondents identified ethnically as Korean.

A study on persistent post-surgical pain (PPSP) or chronic post-surgical pain indicates there is a growing awareness of the potential for PPSP in pediatric populations. However, both this study and an older study suggest that neuropathic pain is considered uncommon in children, but surgical events at an early age can have long-lasting consequences on the patient’s subsequent sensitivity to pain. Additionally, the study on PPSP reports that no study has found an effect of gender on the incidence of PPSP. However, the older study does indicate that women have a greater incidence of all pain conditions (including neuropathic pain), but reports there is little information on the incidence of PSN and gender.

Disease History/Causality

At its most basic, neuropathic pain is a result of a lesion or disease of the somatosensory system. De Fonseca et al. indicate in their review that PSN results from surgical injury of large peripheral nerves. They go on to present the following manner in which PSN genesis would be present after peripheral nerve injury:

Denervated Schwann cells and macrophages produce local and systemic cytokines that signal pain at the site of the nerve injury.

• Injury site neurons act as sites of spontaneous ectopic excitability in sensory fibers.

Sensitivity, responsiveness, transmission, and survival of the sensory neurons are altered by changes in the expression of dorsal root ganglion genes.

Altered activity and gene expression occur at the spinal cord posterior horn, producing central sensitization.

• Sensory flow becomes amplified through the loss of inhibitory neurons as microglia are activated.

• There is a modulation of impulse transmissions to the brain stem from the spinal cord.

• Mood, behavior, and autonomic reflex are modulated by the limbic system and hypothalamus.

• A pain sensation is generated in the cortex that is modulated by previous and normative experience as well as expectation, which converge to determine how patients feel.

• Additionally, there is a predisposition (possibly, but not necessarily genetic) that affects how patients react to treatment.

De Fonseca et al. note that there have been many pathophysiological mechanisms offered to explain pain states, but the key factor in the reviewed literature is the onset of spontaneous or ectopic activity in injured sensory neurons. De Fonseca et al. assert that the ectopic discharge may originate in the injured area of the axonal segment, but most ectopic discharges seem to originate in the dorsal root ganglion. PSN appears after injuries to the nervous, spinal cord, or brain sensory transmitting systems. This would correlate with the findings of the sarcoma study that posits that such surgery often results in nerve injuries as part of the sarcoma removal.

Additionally, de Fonseca et al. note that there are predictive factors for the onset of PSN. Those factors are psychologic and neurophysiologic aspects, genetic susceptibility, psychosocial factors (e.g., pain expectation, fear, previous memories, social environment, work, and physical activity levels), intraoperative manipulation of tissues and nerves, severe and long-lasting pain before surgery, and pain intensity in the immediate and late post-surgical period.

Conclusion

One Brazilian study reports that the incidence of PSN was 13.4%. Another study found that 25% of patients who underwent sarcoma surgery reported PSN. In the Brazilian study, patients suffering from PSN are mostly female, middle-aged, and ethnically Pardo. In the second study, patients are mostly male; the mean age at the time of surgery was 36, and the mean age at the time of the questionnaire was 43. A review of the literature indicates that PSN is a result of surgical injury of large peripheral; such as the kind of injury that would result from sarcoma removal.
Part
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Part
02

Post-Surgical Neuropathic Pain, Part Two

The available treatments for post-surgical neuropathic pain include the use of anticonvulsants, tricyclic antidepressants, opioids, and NMDA-receptor antagonists. We found only one credible source which specifically deals with the treatment of post-surgical neuropathic pain. However, it was published in 2008 and we had to compare the information obtained from it with other recent sources. The recent sources either discussed the treatment of neuropathic pain or post-surgical pain in general.
We only selected the available treatment methods that are present in the first source and at least one other recent source to ensure that they are meant for post-surgical neuropathic pain. We also included the effectiveness of the treatments as well as unmet needs of patients suffering from the condition. Below are details of our findings.

Available treatments and their Effectiveness

Anticonvulsants such as gabapentin (Neurontin) and pregabalin (Lyrica), and tricyclic antidepressants are recommended as the firstline medication for the treatment of post-surgical neuropathic pain. They are usually effective in calming neuropathic pain from surgery which cannot be managed by regular painkillers. However, the dosage required to treat neuropathic pain varies widely for all first-line drugs. This is due to the fact that neuropathic pain is complex, and drugs are poorly tolerated in a good number of patients. "Hence, there is a growing need for newer medications to treat neuropathic pain."
Opioids like Tramadol are recommended as secondline medication. Opioids should be used if the firstline drugs are not effective. Opioids have side effects like dizziness, nausea and constipation, they can also be addictive. According to a 2016 research study of knee replacement patients, 53% of them who used to take opioids both before and after their surgery were still using them after six months. Among patients who were not taking opioids before surgery, 8% continued to use them after their surgery.
NMDA-receptor antagonists drugs include magnesium, ketamine, amantadine, memantine, and dextromethorphan. Ketamine is a strong NMDA-receptor antagonist which is effective in the treatment of post-surgical neuropathic pain. Significant pain reduction for about six months after surgery has been witnessed with intravenous ketamine in some patients. However, it also results in “undesirable psychomimetic symptoms such as hallucinations, sedation, and often needs admission”. The use of intravenous magnesium requires monitoring during treatment as well. Hence, only hospitalized patients can be treated with it.

Dextromethorphan and amantadine are uncompetitive NMDA-receptor antagonists” without any serious side effects. However, they have never been popular for clinical use in the treatment of neuropathic pain. Memantine was recently recommended as a drug for the treatment of neuropathic pain and it has been reported to be a safe NMDA-receptor antagonist which can be used to treat neuropathic pain where conventional pain drugs and treatments were unsuccessful. However, there is inadequate data on its use in the treatment of routine neuropathic pain conditions.
Many of the above medications are generally used for off-label treatments. Unfortunately, many patients suffering from neuropathic pain usually react poorly to standard pain treatments and their condition might occasionally become worse with time rather than better. It could also result in serious disability in some patients. A multidisciplinary approach which includes the combination of different therapies, however, could be effective in bringing relief to patients of neuropathic pain.

Unmet needs of people with post-surgical neuropathic pain

In a research study conducted in the US, some post-surgical neuropathic pain patients “reported high pain scores, which were associated with poor health utility, sleep, mood, and function, as well as high health care resource utilization and costs”. That was an indication of an unmet need for the effective management of post-surgical neuropathic pain. During the study, it was found that opioids were the most commonly prescribed drugs. That was unusual as opioids are generally regarded as second-line drugs in the treatment of post-surgical neuropathic pain. They are to be used only after the failure of first-line drugs. The high opioid use also suggests an unmet need in the proper use of drugs for the management of post-surgical neuropathic pain.
Memantine, an NMDA-receptor antagonist drug, was recently recommended as a newer medication for the treatment of neuropathic pain. There is an unmet need to conduct larger trials to provide more reliable proof of its effectiveness in the treatment of the condition.


Sources
Sources