Current pain medicine practitioners employ a combination of non-pharmacological, pharmacological, and interventional strategies to manage a patient’s pain. Current trends in pain medicine focus on multidisciplinary care. In the current model, pharmacological treatment remains a pillar for the management of pain. Multimodal analgesia, or the concurrent use of multiple medications employing different mechanisms of action, has been associated with improved analgesia with fewer side effects [21, 22]. With the rise of telehealth and other methods of healthcare delivery growing during the pandemic, multimodal analgesia may play an increased role in the post-COVID era, and is therefore important to review.
Non-Opioid Analgesics and COVID-19
-
Acetaminophen/paracetamol:
Acetaminophen/paracetamol acts both centrally and peripherally to reduce prostaglandin synthesis from arachidonic acid via inhibition of the cyclooxygenase isoenzymes. The medication should be considered alone or in combination with non-steroidal anti-inflammatory drugs (NSAIDs) in the management of mild-to-moderate pain as part of multimodal analgesia [19]. Paracetamol can also be used safely to alleviate symptoms of COVID-19 such as fever, headache, and acute or chronic pain. However, caution must be observed due to liver toxicity at high doses of paracetamol [23].
-
NSAIDs
Non-selective NSAIDs (e.g., ibuprofen, naproxen, and indomethacin) are effective for mild-to-moderate pain through inhibition of cyclo-oxygenage-1 (COX-1) and cyclo-oxygenage-2 (COX-2) enzymes leading to a reduction of prostaglandins. Prostaglandins mediate pain, fever, inflammation, and swelling, and have a key role in gastric protection and hemostasis [19, 24].
Prolonged use of non-selective NSAIDs is associated with a higher risk of adverse effects including gastrointestinal disease (dyspepsia, gastritis, peptic ulcer disease, and ulceration), renal toxicity, inhibition of platelet function, and respiratory bronchospasm in some patients with asthma [19, 24].
NSAIDs are relatively contraindicated in patients with respiratory disorders, as in acute respiratory infections. NSAIDs have also been implicated in acute myocardial infarction and risk of stroke in rare cases [25]. Specific concerns related to COVID-19 and the use of NSAIDs have hypothesized that NSAIDs may upregulate entry through the angiotensin-converting enzyme (ACE) 2 receptors, thereby increasing susceptibility to the virus. These data are still inconclusive [25].
Selective COX-2 inhibitors (e.g., etoricoxib and celecoxib) COX-2 inhibitors specifically target prostaglandins that mediate pain and inflammation and have less gastric side effects compared to their non-specific NSAID counterparts. COX-2 inhibitors are as effective as classical NSAIDs for the treatment of mild-to-moderate pain, but have been associated with an increased cardiovascular risk [21, 22].
NSAIDs and COVID-19 Cytokine storm is a poorly understood exaggerated response involving an uncontrolled release of pro-inflammatory cytokines [26]. Adverse outcomes of COVID-19 have been linked to this exaggerated inflammatory response [25].
As cytokine storm has been postulated to play a major role in adverse outcomes of severely ill patients with COVID-19, anti-inflammatories ranging from NSAIDs to glucocorticoids to hydroxychloroquine and others may be beneficial to reduce inflammation before it overwhelms the body’s systems [27]. While an anti-inflammatory can reduce inflammation, it may have a limited or poorly understood effect on cytokine storm, which involves multiple cytokines and complex interactions. In other words, an anti-inflammatory agent may affect certain cytokines but not others [28]. Currently, as of June 2020, randomized trials are taking place for medications like canakinumab [29], ruxolitinib [30], and others that focus on specific cytokines.
However, the role of anti-inflammatories that broadly affect cytokines, such as NSAIDs, is unclear. To date, there is no strong evidence that NSAIDs must be avoided in all patients diagnosed with COVID-19. Clinicians must weigh these choices on an individual basis. Even if anti-inflammatory therapy were to be advocated, it is not yet clear which medication therapies provide the most benefit. Similarly, at which point during the disease, at what doses, and for what duration anti-inflammatory therapy should be used is still unknown [25, 31].
Currently, insufficient evidence exists to establish a link between the use of some NSAIDs such as ibuprofen and susceptibility to contracting COVID-19 or the worsening of its symptoms [23, 32].
Alternatively, paracetamol/acetaminophen can be used instead of NSAIDs. Caution must be observed due to liver toxicity at high doses of paracetamol [25]. However, the antipyretic effect of both paracetamol and NSAIDs may mask the symptoms associated with COVID-19 such as a rising fever and thus may delay the diagnosis and rapid management of the infection [33].
Practical tips for the use of NSAIDs during the COVID-19 pandemic:
-
For patients with COVID-19, newly prescribed oral NSAIDs might only be used intermittently over a very short period of time [34].
-
Clinicians must consider a patient’s whole picture with the addition of any new medication, and avoid NSAIDs in those patients where NSAIDs are contraindicated, such as those with peptic ulcer disease or renal dysfunction [25].
-
Discontinuation of prescribed NSAIDs for chronic pain conditions is not recommended at this time. There is no reason to fear it might increase their risk of contracting COVID-19 or exacerbate symptoms if previously on treatment [35].
-
Acetaminophen (paracetamol) has been proposed as an alternative to NSAID use, but there are also issues with acetaminophen toxicity in high doses [36].
Opioids and COVID-19
Opioids are a treatment for moderate-to-severe pain and both cancer and non-cancer pain. Although consensus exists about their effectiveness in the treatment of chronic cancer pain, long-term opioid use for chronic non-malignant pain is controversial [37]. Opioids have also been used for a wide range of painful conditions including both nociceptive and neuropathic pain [22, 38]. Of importance, in current pain practice, opioids are generally used as only part of a treatment plan, which includes physical therapy, pain psychology, interventional procedures, and other ancillary therapies.
Opioids produce their effect by acting as agonists at various opioid receptors found in the brain, spinal cord, and sites outside the central nervous system (CNS). Opioids are available in different forms and can be used by different routes of administration, e.g., oral, sublingual, intravenous (IV), intramuscular (IM), subcutaneous (SC), transdermal, and neuraxial. Most of the opioids have a similar spectrum of adverse effects, e.g., respiratory depression, sedation, nausea/vomiting, constipation, physical dependence, and opioid use disorder [19, 22, 38]. There is also evidence suggestive that chronic opioid use can produce a chronic pain state [39].
Opioids and the immune system Morbidity and adverse outcomes from COVID-19 are more common in immune-compromised patients. The effects of opioids on the immune system are complex and depend on the type of opioid, dose, nature of immunity, and the patient’s situation [40]. In opioid-tolerant patients, opioids are linked to infections like pneumonia [41]. However, pain itself may have an immunosuppressive effect. With that in mind, it is possible that the use of opioids to relieve acute and chronic pain may actually enhance the immune response [42]. Providing adequate analgesia should be achieved without significant adverse events, and opioids with minimal immunosuppressive characteristics may be reasonable options in such situations where opioid use is indicated. Buprenorphine is highly recommended [43], tramadol and oxycodone can be used as a second option [44], while morphine and fentanyl are not recommended due to side effects and addiction potential [43, 45].
Opioid-tolerant patients Many services and guidelines have permitted opioid prescriptions via telemedicine visit or E-health to facilitate delivery and reduce the risk of opioid withdrawal. This is also allowed for patients who need to increase the opioid dose because of a reasonable causes. For patients who may have run out of medications, assessment of withdrawal symptoms and signs can be challenging. Some signs, like agitation, diaphoresis, piloerection, and elevated pulse rate can be observed remotely by the patient or a caregiver [46, 47].
Patients at risk of opioid withdrawal should be scheduled for an in-patient visit. Non-opioid strategies to prevent withdrawal (e.g., using clonidine) are alternative options when there is difficulty in getting the opioids. Emphasis must be placed on the appropriate prescription of opioid medications, as the quarantine and social distancing with the current pandemic has been postulated to lead to worsening of disorders like alcohol dependence and opioid use disorders [46, 47].
Opioids for acute pain Opioid use via telemedicine must be used sparingly and only when absolutely indicated. Current recommendations for non-malignant acute pain recommend a maximum of 7 days [48, 49]. For patients with acute pain or those with severe exacerbation of chronic pain and needing short-term opioids, a short electronic prescription after evaluation via telemedicine or E-health is reasonable. Before prescription, red flags associated with COVID-19 including lethargy, nausea and gastrointestinal symptoms must be excluded [50]. If patients need opioids for longer durations or to be continued, an in-patient visit is recommended to identify patients who might be candidates for opioid prescription or other interventions for pain managements [48, 50].
Transdermal dermal opioids (TD) The fevers and elevated temperature associated with symptomatic COVID-19 may increase absorption from transdermal opioid patches (e.g., fentanyl and buprenorphine) and could increase opioid side-effects [50]. Patients who are prescribed transdermal opioids with increased side effects who become increasingly drowsy or somnolent may require patch strength to be reduced, or alternatively replaced, with short-acting opioid formulations. This should continue until symptomatic infection is resolved and the fever is lowered [50].
Opioids in special situations For patients with implantable intrathecal pumps in need of refill, an in-patient or clinic appointment is required. If the dose has been stable for a long period of time, around the order of 1 year, and the patient does not complain of worsening pain or side effects, an in-home pump refill may be done by special services like home health [51].
Practical tips for opioids with COVID-19 pandemic:
-
In all patients receiving opioids chronically, it is recommended that an in-patient visit be performed within 2–3 months for patient’s evaluation after a prescription has been provided.
-
Before increasing the dose of chronic opioids, it is important to differentiate between disease progression from other opioid drawbacks, e.g., tolerance and hyperalgesia.
-
Opioids should be used for pain relief only, while the use of opioids to alleviate non-pain conditions, e.g., sleep, anxiety, or depression should be monitored and discouraged [51].
-
Opioids are also cough suppressants, and this may mask or delay the initial presenting symptoms of COVID-19 infection, and extra importance must be placed on monitoring of respiratory symptoms suggestive of COVID-19 while on opioid therapy.
-
Lethargy, nausea, and gastrointestinal symptoms that are associated with COVID-19 infection could be worsened by prescribed opioids, as well as other medication for neuropathic pain like gabapentin or pregabalin [50].
Interventions Pain Therapy and COVID-19
Pain interventions are typically minimally invasive procedures that when appropriately indicated, relieve acute and chronic pain as well as minimize the use of analgesics. Interventional pain management is often performed on an outpatient basis and can be used for diagnostic, prognostic, or therapeutic purposes. Image guidance such as ultrasound, fluoroscopy, or computed tomography can be used during the intervention when clinically indicated [19, 52].
Suggested definitions for the classification of urgency in interventional pain procedures [51]:
-
Elective These procedures are not time-sensitive; a patient normally could wait greater than 4 weeks to undergo the procedure based on the unique circumstances and no significant harm to the patient is anticipated with postponement of the procedure.
-
Urgent elective These procedures are time-sensitive; a patient normally could not wait months to undergo the procedure, for unique circumstances, where a delay of the procedure for more than a few weeks could potentially lead to a worsening of a patient’s condition.
-
Urgent These procedures are time-sensitive; a delay in proceeding with a procedure would result in significant exacerbation and worsening of the condition such as emergency visit, inpatient hospitalization, or unintended consequence of analgesics.
Corticosteroids and COVID-19
Corticosteroids are immuno-suppressants that have been linked to increased infection risk. Immuno-suppression has been reported with systemic as well as epidural steroids, putting patients at an increased risk of infection [51,52,53,54]. Moreover, a significant number of chronic pain patients are on opioids, well-documented immuno-suppressants. Treating such patients with pain procedures using small amounts of non-systemic corticosteroids may minimize the need for opioids [53, 54].
Randomized controlled trials (RCT) have shown that epidural steroid injection doses exceeding 40 mg methylprednisolone, 20 mg triamcinolone, and 10 mg dexamethasone provide no recognizable pain relief difference compared to lower doses. Some studies have indicated no additional benefits for doses greater than 10 mg triamcinolone or 4 mg dexamethasone [52, 55]. However, Rainvith et al. [56] showed a strong correlation between the epidural volume and pain relief irrespective of the steroid dose.
During the COVID-19 pandemic, physicians may continue to perform epidurals and other injections for selected patients when indicated. Providers should keep in mind, however, that there is no clear evidence of a causative effect between spinal procedures without steroids and the increased risk of infection, suggesting an increased risk of infection with corticosteroid use [53].
Regarding intra-articular injections, clinical trials showed no difference between 40 and 80 mg of triamcinolone for knee injections [57]. Also, it is important to note that many simple procedures such as trigger point injection, steroids has no additional benefit compared to saline [58].
Practical tips for interventional pain therapy with COVID-19:
-
1.
General preparations: The general guidelines and infection control precautions according to the WHO recommendations must be followed in order to minimize probability of harm during the COVID-19 pandemic. Patients should be informed of the possible risk of infection before intervention. All patients should done face coverings, and those with respiratory symptoms or fever should follow up with their primary physician. All surfaces should be clean and disinfected in the patient care environment between each patient encounter to limit surface-to-person spread of COVID-19 [59, 60].
-
2.
High-risk patients Procedures should be limited to urgent or emergent cases, as outlined above. The procedure should be conducted in a room designated for such purposes (e.g., negative pressure room). Due to increased risk, physicians who treat high-risk patients should be adequately protected and the use of N95 masks should be highly considered.
After the procedure, the patient should be monitored in the same room until they can be transferred to an appropriate isolation area or discharged home to shelter in place. Appropriate precautions should be taken during the removal of protective gear [59, 60].
-
3.
Personal protective equipment (PPE) We strongly consider the use of surgical facemasks, eye shields, and gloves during patient care. N95 masks should be used for emergent procedures or high-risk patients, e.g., COVID-19 symptoms or infected patients, or positive contacts. During the procedures, sterile attire must be donned, and this attire should be discarded after patient treatment [59, 60].
-
4.
Pain procedures The factors involved in risk stratification include pre-visit risk reduction, exposure time, and body region exposed. For the most common procedures performed, patients are positioned face down, and the contact area is limited and sterilely prepared. Providers may request that patients shower before receiving injections in high-risk situations [59, 60].
In immunocompromised and high-risk patients, epidural injection with the lowest dose of steroids or without steroids should be considered. For procedures with the potential for aerosolization such as intranasal sphenopalatine ganglion blocks and intra-oral injections, N95 masks should be used as recommended. Deep sedation that may require airway support should be avoided to avoid respiratory distress [59, 60].
-
5.
Staffing plans The goal of staffing plans should be to minimize "unnecessary” exposure of hospital staff to patients, and to themselves. Only those essential to the physician–patient interaction should be allowed to enter the hospital and patient care areas. Along these lines, procedures should be performed with the minimal number of personnel and staff, ideally by a physician with extensive experience in minimizing risk exposure. It is also recommended to designate one physician to perform all procedures during the same session to minimize potential physician and patient exposure [60, 62].