Ketamine for Chronic Pain

Abstract

The treatment of chronic pain is a chronic problem for many specialities. It is generally based on an approach with antidepressants, anti-epileptics and opioids as drugs of first choice. It has been worked by many different protocols. Ketamine, which is known as a good anaesthetic, has been used for chronic pain. When the pain has a neuropathic component, ketamine is a promising treatment for pain management. Ketamine: by inhibiting the N-methyl-D-aspartate receptor and having some other effects like enhancement of descending inhibition and anti-inflammatory effects at central sites, takes part in chronic pain management. Besides having analgesic effects, there are some concerns about the side effects of ketamine. Some psychedelic symptoms as hallucinations, memory defects, panic attacks, nausea and vomiting, somnolence, cardiovascular stimulation and sometimes hepatoxicity may be seen in patients. Ketamine is generally well-tolerated in clinical settings. Close monitoring of patients receiving ketamine should be mandatory in order to be aware of central nervous system, haemodynamic, renal and hepatic symptoms as well as abuse.

1. Introduction

Chronic pain is classified as pain that lasts longer than three to 6 months. Besides medical treatment, it consists of many other issues, such as social, economic and psychological. The treatment of chronic pain is a chronic problem for many specialities; it is generally based on an approach with antidepressants, anti-epileptics and opioids as drugs of first choice. Still, there is no right choice for these patients and 60–70% remains untreated [1, 2].

Chronic pain management is arguably at its most effective when a multidisciplinary approach is used. Ketamine can optimise other (non-opioid) medications by reducing opioid requirements [3].

The socioeconomic burden due to chronic pain is another problematic issue and cannot be overestimated. In Europe, the reported burden of chronic pain is nearly equally steep, with the point prevalence estimated to be 25–30% [4].

Ketamine has been on the market as an alternative to phencyclidine since 1960s. In 1965, it is used as an anaesthetic. Ketamine produces dissociative anaesthesia as well as analgesia and amnesia. Because of its side effects like, the induction of a psychedelic state causing agitation, hallucinations and panic attacks, ketamine has limited use in contemporary anaesthesia.

Ketamine is a phenylpiperidine derivative structurally related to phencyclidine with 2(2-chlorophenyl)-2-(methylamino)-cyclohexanone as its chemical structure. There are two different forms of ketamine: the racemic mixture (Ketalar®, Pfizer Inc., available in the US since 1966) and the S(+) enantiomer (S-ketamine or Ketanest-S®, Pfizer Inc.).

Ketamine is a potent N-Methyl-D-aspartate (NMDA) antagonist and is generally used in the treatment of acute and chronic pain, sedation, induction and maintenance of anaesthesia and ICU sedation [5]. It exerts its NMDA antagonism by binding to the phencyclidine receptor site when the channel is open. Its property to inhibit these receptors, it is postulated that ketamine can help treat chronic neuropathic pain [6]. Also, ketamine can be used as an antidepressant, making it useful in the concomitant treatment of pain and depression [7].

Ketamine is known to prevent central sensitization, so infusions of ketamine started intraoperatively and continued into the early postoperative period might prevent chronic postoperative pain, which is a problem impacting approximately 20% of surgical patients [8]. Ketamine, by inhibition of the N-Methyl-D-aspartate receptor (NMDAR), causes strong analgesia in neuropathic pain. Also, NMDAR is involved in the process of chronification of pain [9].

Ketamine also interacts with other receptors such as opioidergic, muscarinic and mono aminergic receptors. But still, little is known about the contributions of these receptor systems to the various effects of ketamine [10].

There are many routes that ketamine can be given; IV, IM, SC, oral, rectal, nasal, transdermal, epidural, or intrathecal [11]. Orally administered ketamine undergoes extensive first-pass metabolism, primarily via N-demethylation, resulting in small ketamine concentrations and large nor-ketamine concentrations in blood and tissue [12].

One of the challenging concepts about chronic pain patients should be treated in an inpatient setting. When outpatient treatment is planned, other issues must be considered like lack of monitoring, increased risk of toxicity and abuse. Smart dosing regimens, patient (and doctor) training, frequent contact and close monitoring of drug are needed for home treatment of ketamine [13].

The multimodal approach is the most effective treatment of chronic pain. Ketamine is often administered together with opioid analgesics, post-operatively and in the treatment of chronic cancer pain.

2. Central pain

Ketamine has been studied for central pain after spinal cord injury. Oral and parenteral ketamine was found to be effective. It reduced continuous and evoked pain in these patients, and it is related to only mild side effects [14]. Ketamine showed an analgesic effect in a case with neuropathic pain after cauda equina trauma [15]. Ketamine was found effective in a patient with central poststroke pain after subarachnoid haemorrhage, besides providing analgesia, ketamine also helped the opioids and anticonvulsants to be tapered and discontinued [16]. The authors used midazolam for premedication and used iv incremental dose. With 50 mg oral dosing nightly, increasing to 50 mg 3 times a day resulted in relief of allodynia and hyperalgesia.

3. Complex regional pain syndromes

Complex regional pain syndrome is a chronic pain condition having both autonomic and inflammatory features. It occurs acutely in about 7% of patients who have limb fractures, limb surgery, or other injuries. Only a small percentage of it turns into a chronic form. This transition is often paralleled by a change from ‘warm complex regional pain syndrome,’ with inflammatory characteristics dominant, to ‘cold complex regional pain syndrome’ in which autonomic features dominate. Many complex mechanisms take role in this period. This may include peripheral and central sensitization, autonomic changes and sympatho-afferent coupling, inflammatory and immune alterations, brain changes, and genetic and psychological factor. Effective management of the chronic form of the syndrome is often challenging. There are reports about epidural use of ketamine in patients with complex regional pain syndromes and refractory to other treatments [16, 17]. Dose for epidural ketamine suggested was 0.3 mg/kg followed by 25 mcg/kg/h with only transient side effects like headache and nausea.

4. Fibromyalgia

Fibromyalgia is a disorder characterised by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. Fibromyalgia is thought to amplify painful sensations by affecting the way your brain and spinal cord process painful and nonpainful signals. Symptoms usually appear after physical trauma, surgery, infection or significant psychological stress. In other cases, symptoms gradually accumulate over time with no single triggering event.

In patients with fibromyalgia, ketamine which is given 0.3 mg/kg iv, showed an increase in endurance and reduction in pain intensity, tenderness at trigger points, referred pain, temporal summation, muscular hyperalgesia, and muscle pain at rest. It is suggested that ketamine by reducing central sensitization, is effective in fibromyalgia.

5. Ischemic pain

Peripheral vascular disease is a common reason of limb pain-causing considerable suffering. In its early stages, it can present as intermittent claudication, but with multiple levels of occlusion rest pain can develop. Patients presenting with critical limb ischemia face a 13% risk of primary amputation. The pain often responds poorly to different treatment strategies including opioids.

As ischemic pain of arteriosclerosis may consist of both nociceptive and neuropathic components, it is generally poorly responsive to opioids. When compared with ketamine with a potent dose dependent analgesic effect (0.15, 0.3, 0.45 mg/kg iv) in clinical ischemic pain but with a narrow therapeutic window, ketamine may show better analgesia in these patients [18]. Also dose dependent side effect such as disturbed cognition and perception recorded for these patients.

6. Neuropathic pain

According to aetiology, neuropathic pain syndromes are heterogeneous; in clinical aspect, they have many similarities. Pain, dysesthesias and hyperalgesia are the main features of neuropathic pain syndromes. Unfortunately, standard pharmacologic therapies are generally insufficient.

Current interest in ketamine focuses on its ability to alleviate chronic pain, especially when chronic pain has a neuropathic component. Chronic neuropathic pain is the most widely investigated indication for IV ketamine. Different doses have been tried between 0.25 and 0.75 mg/kg iv. Most side effects are observed with high doses. Neuropathic pain results from lesions of the somatosensory nervous system causing alterations in structure and function so that pain occurs spontaneously and responses to noxious and innocuous stimuli are amplified [19].

Another condition that generally manifests with neuropathic pain is chronic diabetes. In mice, this can be modelled with high-dose injection of streptozotocin which selectively kills pancreatic beta cells through DNA alkalization. Ketamine when given systemic infusion at 20 mg/kg/day for 5 days showed to reduce heat and mechanical hyperalgesia for several weeks following treatment.

7. Acute on chronic neuropathic pain

Ketamine is frequently used for managing acute episodes of refractory neuropathic pain. In these situations, generally, large doses of opioids are used which leads to development of severe hyperalgesia. The mechanism of opioid induced hyperalgesia is not certain, one of the leading theories is overactivation and stimulation of the NMDA-receptor, so this proposed mechanism would explain why NMDA receptor modulators such as ketamine are effective in treating the condition. Ketamine with 10 mg/h iv suggested for opioid hyperalgesia. Also, subcutaneous administration can be a good alternative for these patients to get time for finding iv access.

8. Orofacial pain

Neuropathic pain related to ‘nerve damage in the trigeminal region’ is one of the chronic pain topics, which generally needs many interventions for pain relief. Ketamine can be an alternative for these kinds of pain issues. NMDA receptor inhibition by ketamine might change the sensitization, so ketamine causes pain relief even after ketamine has been eliminated from the body. The optimal dose suggested as 60 mg per oral, 6 times a day found [20]. Some side effects like dizziness and fatigue were well tolerated.

9. Phantom/stump pain

After amputation of a limb, most amputees suffer from stump and phantom limb pain. Many medical and surgical therapies have been tried, but only a few treatments have been found to be effective. Both peripheral and spinal mechanisms have been accused of underlying mechanism. Studies show that C-fibre input may induce a central hyperexcitability in dorsal horn neurons. There is evidence that this hyperexcitability in part is mediated by excitatory amino acids acting at NMDA receptor sites and that excitatory amino acid receptor antagonists may block this central hyperexcitability and its clinical manifestations.

Case series and case reports support ketamine use in stump and phantom pain. Ketamine showed a significant increase in pressure thresholds and reduced hyperpathia. Especially for patients who did not benefit from conventional treatments, iv ketamine was very effective. Doses such as 0.1 mg/kg iv over 5 min then infusion of 7 g/kg/min for 45 min and 0.125–0.3 mg/kg iv then continuous sc infusion 0.125–0.2 mg/kg/h for maintenance showed effective results. Also, other papers support the use of oral ketamine to control phantom pain (50 mg/6 hr) [21].

10. Postherpetic neuralgia

Nerve injury may lead to persistent pathological pain with hyperalgesia and pain evoked by non-noxious stimuli. Long-lasting hyperexcitability in nociceptive neurons initiated by increased activity in primary afferents may play a role in the pathogenesis of nerve injury pain. In particular, the N-methyl-o-aspartic acid receptors may be important for the development of long-lasting changes in neuronal excitability. NMDA receptor blockers inhibit the progressive increase in action potential discharge (wind-up) and neuronal hyperexcitability produced by repeated stimulation of small-diameter primary. NMDA receptor blockers also inhibit nociceptive behaviour in animals caused by nerve injury.

Ketamine is effective for pain relief in postherpetic neuralgia. Ketamine produces significant pain relief and also reduces allodynia and hyperpathia [22]. Relief of continuous pain was observed at the smallest dose but was most marked at the largest (0.05, 0.075, 0.1, 0.15 mg/kg/h. sc). The number and severity of spontaneous pain attacks are also reduced. Ketamine administration showed even complete resolution of ophthalmic postherpetic neuralgia [23].

11. Headache, backpain and others

Patients with refractory chronic migraine suffer from continuous pain and nonpainful symptoms, substantial disability, and have generally failed treatments with multiple medications. Patients with severe pain have often failed typically inpatient or outpatient infusion treatment, so few options remain for them.

Ketamine use for headaches has demonstrated benefits. Subcutaneous ketamine of 80 μg/kg was associated with an approximately 50% reduction in acute migraine-related pain and an approximate 75% reduction in chronic migraine-related pain [24].

Unfortunately, there was weak or no evidence supporting ketamine infusions for immediate improvements in pain management of mixed neuropathic pain, PLP, PHN, fibromyalgia, cancer pain, ischemic pain, migraine headache and low-back pain. Evidence only supports ketamine infusions for intermediate or long-term improvements in pain management of CRPS [25].

Some reports suggest that ketamine decreases the rate of chronic postoperative pain when administered as a pre-incisional dose (0.15–1 mg/kg iv) followed by an intraoperative infusion, and intravenous ketamine has been shown to significantly reduce chronic pain incidence following certain types of surgeries [26].

Multimodal approach to chronic pain is found to be the most effective treatment. In general, ketamine is administered with opioids, post-operatively and in the treatment of chronic cancer pain. A Cochrane review showed that ketamine is effective in reducing morphine consumption, and is related to less pain and less nausea and vomiting [27]. Also, ketamine positively affect opioid treatment in cancer pain [28]. The ability of ketamine to reduce the incidence (and severity) of opioid side effects is important as side effects reduce patient compliance. So, an opioid-ketamine combination may be useful in non-neuropathic pain states (e.g., in the palliative setting) or in mixed nociceptive/neuropathic pain states (e.g., in cancer pain).

Studies show that ketamine has also anti-depressant effects [29]. In fact, clinical studies showed that a subanaesthetic dose of ketamine produces antidepressant effects Ketamine has a positive effect on depressive symptoms in otherwise therapy-resistant patients. Because depression and chronic pain share common mechanistic pathways, Most chronic pain patients face depression or depression-like symptoms.

In fact, the treatment of chronic pain may serve two purposes, treating the pain and ameliorating the depressive symptoms. When the pain is treated and the depression simultaneously resolves, or the reverse is true.

Some experimental reports conclude that ketamine has also anti-inflammatory, neuroprotective and anti-tumour effects [30].

12. Intravenous ketamine for chronic pain

Intravenous ketamine infusions have the advantages of avoiding first-pass metabolism and also controlling the way of administration. But this requires inpatient settings allowing the healthcare team to monitor for adverse conditions and track treatment efficacy.

A meta-analysis including seven different studies examining both neuropathic and non-neuropathic pain conditions showed a significant analgesic effect for intravenous ketamine infusions. The median ketamine dose of 0.35 mg/kg was reached after 5 h. In these studies, maximum analgesic effect was observed between 48 h and 2 weeks post-infusion. The studies showed no efficacy difference between ketamine as a sole agent or adjuvant therapy [31]. This meta-analysis reported that ketamine shows significant promise for the treatment of a wide variety of chronic pain conditions, including neuropathic and non-neuropathic. Due to the long-acting nature of ketamine’s analgesia, outpatients treatments could be effective with visits required as frequently as infusions are needed.

Ketamine can be used as a third-line agent in intractable cancer pain. In a case study of cancer patients with intractable pain, ketamine infusions at a rate of 1.5 mg/kg/day reduced total daily morphine use by 50% after patients were sent home with ketamine/morphine pain pumps [32].

13. Oral and nasal ketamine for chronic pain

Oral and nasal formulations generally do not need are direct physician supervision in contrast to infusions, so oral and nasal formulations are more desirable for management of long-term pain conditions. Despite requiring higher doses due to extensive metabolism, oral administrations have also been found to be effective in providing analgesia.

A study with a daily dose of 2 mg/kg, ketamine showed reduction in pain in two-thirds of patients while one-half of patients reported some adverse event [33].

Intranasal ketamine, although now mostly taken part in the treatment of depression, has also been tried for management of cancer pain. Intranasal ketamine was found to be successful in 65% of breakthrough cancer pain patients and achieved a Numerical Pain Intensity Scale (NPIS) score that was at least 40% lower than pre-treatment levels [34].

14. Ketamine as a topical agent

Ketamine as a topical agent may be preferred for patients in whom systemic ketamine administration via oral or IV routes is not desirable administration. Topical application provides the benefit of keeping plasma concentrations and therefore potential side effects at a minimum.

Topical ketamine has been tried in chronic regional pain syndrome, studies reported effective reduction in pain measures, tactile allodynia and Visual Analog Scale pain score. Besides being a good alternative in pain management, still, there is concern about the systemic levels of ketamine [35].

15. Concerns

Ketamine besides being an anaesthetic is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Inhibition of the N-methyl-D-aspartate receptor and probably some other mechanisms like enhancement of descending inhibition and anti-inflammatory effects at central sites results in strong analgesia even with low doses.

The side effects of ketamine noted in clinical studies include psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence, cardiovascular stimulation and hepatoxicity. There are also risks ranging from the bladder and renal complications to persistent psychological behaviour and memory defects by the increase in ketamine usage. Also, abuse is another problem.

Cognitive side effects of ketamine frequently limit its use. Since its discovery, ketamine was known to produce dissociative and psychomimetic effects. These effects are also responsible for the continued abuse of ketamine [36].

Studies showed that ketamine produces structural and physiological changes in the brain, even a decrease in grey and white matter volumes in the pre-frontal cortex and white matter degeneration in the left temporoparietal lobe has been reported [37].

Regardless of the mechanism of these cognitive disorders, many research has been done to find out what drugs may be able to prevent them. Several of these studies have demonstrated that benzodiazepines, specifically midazolam and haloperidol, reduced undesired psychotic side effects and nausea associated with ketamine administration [38].

Cystitis related to ketamine use is another problem, especially for long term users. The increase in neurotrophin in bladder tissue accused to cause the chronic inflammation of the bladder and urinary tract in ketamine cystitis [39].

Elevation of serum liver enzymes has been reported in patients receiving ketamine infusions, but these levels decreased back to baseline within 10–14 days following treatment [40].

Due to ketamine’s central inhibition effect of norepinephrine reuptake in adrenergic nerves, an increase in cardiac output via elevations in heart rate, systolic blood pressure, and diastolic blood pressure can be observed. Also, ketamine acts as a sympathomimetic on the cardiovascular system [41].

Because of dissociative and hallucinogenic effects of ketamine, it has been abused. Even therapeutic doses are generally less than street-use doses, ketamine still maintains addictive potential.

In clinical settings, ketamine is generally well tolerated, especially when benzodiazepines are used to suppress the psychotropic side effects. Patients receiving ketamine should be monitored closely, especially for CNS, haemodynamic, renal and hepatic symptoms as well as abuse. Until definite proof is obtained ketamine administration should be restricted to patients with therapy-resistant severe neuropathic pain.

16. Conclusion

Ketamine as an analgesic can be used for several indications and in many ways. It may be used most effectively to reduce the symptoms of allodynia, hyperalgesia and hyperpathia rather than acting as a traditional analgesic. This could be consistent with NMDA receptor blockade limiting or reducing central sensitization, although the ability of ketamine to interact with such a wide variety of receptors means that this is currently only speculative.

There are various dose regimens for different application ways for ketamine. Most of the data is based on case reports. Still, there are also concerns about side effects and with different premedication like lorazepam or midazolam, most of the side effects may resolve.

The data provides encouraging suggestions about ketamine for chronic pain situations. To talk about pros of ketamine for chronic pain management:

• Ketamine is tried for many types of pain and found most useful

• Pain related to neuropathies can be relieved by ketamine

• Ketamine can be effective for pain where opioids are ineffective, and hyperalgesia occurred cause of opioids.

• Ketamine can be used during the perioperative period both for acute analgesia management and for preventing chronic pain.

• Ketamine can be applied by many routes; epidural, subcutaneous, intravenous.

• Ketamine has an antidepressant effect, which plays an important role in the management of chronic pain.