The present study demonstrates that the patients with EDS-HT/JHS undergoing CCF who received OFAplus postoperative administration of lidocaine, ketamine and dexmedetomidine infusions presented a significant reduction in pain during the first 6 days of postoperative and at the time of the hospital discharge compared with the group managed with opioid-based anesthesia plus postoperative analgesia with intravenous morphine. Moreover, throughout the hospital stay, the percentage of patients who required methadone rescue to treat severe breakthrough pain was considerably lower in the OFA-plus group, as well as the total doses of methadone.
Due to the limitations of a retrospective study, there were difficulties in achieving some of our goals. The patients of the OFA-plus group used oral sufentanil by PCA as part of their postoperative analgesia protocol, and patients of OP group received morphine in continuous infusion plus PCA bolus. The difficulty found in establishing a comparison in the consumption of opioids by PCA between both groups during the first 6 postoperative days was solved using the concept of equivalence potency between opioids, and also grouping the opioid requirements by the ranges of clinical doses used.
During the first postoperative day, PCA requirements of sufentanil in the OFA-plus group were lower than the equivalent doses of morphine required in the OP group. This finding is consistent with the published literature related to the effects of the OFA on the reduction of opioids in the first 24 hours after surgery. Maintaining intraoperative homeostasis (normovolemia, normothermia, normoglycemia, hemodynamic stability) in conjunction with the doses of lidocaine, ketamine and dexmedetomidine used during surgery probably had a significant effect on the attenuation of intraoperative stress, systemic inflammatory response and pain on the first postoperative day (8,12).
Although there were no differences in sufentanil or morphine equivalent requirements on the 2nd, 4th and 6th day, VAS score was significantly lower in the OFA-plus group during the first postoperative week. The complexity of the patients studied and the type of surgery made analgesic treatment without opioids extremely difficult for pain control in the first days after surgery (11,13).
Studies of OFA in patients undergoing spinal surgery show controversial results in terms of the postoperative reduction of opioids, the recovery time, the complications, and the length of hospital stay (8,9,10).However, there seems to be more agreement about the perioperative use of non-opioid coadjuvants as part of a multimodal analgesia protocol to achieve enhanced recovery after spine surgery (11,13,14).
We cannot affirm that OFA management is an independent factor in reducing postoperative pain. However, OFA management plus postoperative use of lidocaine, ketamine, and dexmedetomidine infusions as part of robust multimodal analgesia can explain our results (10).
Intravenous lidocaine, ketamine, and dexmedetomidine have analgesic mechanisms mediated by a strong systemic anti-inflammatory effect and other multiple anti-nociceptive pathways (i.e., reduction of inflammatory biomarkers by direct action on cell membrane of monocytes, neutrophils and mast cell, PKC-mediated reduction of Ca++intracellular influx and K+A-channels, action over cholinergic, adrenergic, GABAergic, NMDAr, and NK-1r pathways). (15-18).
In the OFA-plus group, these coadjuvants were administered intraoperatively and during the first postoperative week. The continued perioperative use of lidocaine, ketamine and dexmedetomidine infusions and the gradual reduction of the doses over one week might overcome the peak of the inflammatory surgical-response, and therefore its effect on pain and Central Sensitization, minimizing opioid exposure, and resulting in a reduction of VAS(6,12,19,20).
In the OP group, morphine analgesia protocol was maintained for 16.0 ± 3.0 days. In the OFA-plus group, the average time of administration of sufentanil by PCA was 7.0±2.2 days. During the remaining time of hospitalization of the OFA-plus group only methadone was used as a rescue pain reliever until hospital discharge.Methadone is an opioid with an unique central nervous system effects (anti-NMDA receptor and inhibition of serotonin and norepinephrine uptake) that may enhance recovery by attenuating the development of hyperalgesia and tolerance. Also, the literature describes that methadone can improve postoperative analgesia and the long-term outcome in patients undergoing posterior spinal fusion surgery (21,22).
There was no difference in the length of the hospital stay (OFA-plus: 19±3.1 days vs. OP 22±2.3 days). However, at the time of hospital discharge VAS score and total opioid consumption were lower in the OFA-plus group. We believe that the results obtained are the consequence of the sum of multifactorial effects because of the administration of OFA, postoperative use of infusions of lidocaine, ketamine and dexmedetomidine, the limited use of sufentanil for less than 8 days, and the use of methadone as the only rescue during the rest of hospitalization.
Patients in both groups had preoperative severe occipital-cervical pain (VAS score OFA-plus: 8.0 vs. OP: 7.0, p = 0.764). Also, a high percentage of the patients in both groups (57.1%) came with medical prescription of strong opioids or a combination of these (p=0.819).
At the time of hospital discharge, the OFA-plus group showed a decrease in opioid requirements in comparison to preoperative doses vs. OP group (p<0.001). The 60.9% of patients in the OFA-plus group showed a reduction in opioid doses, whereas 63.2% of patients in the OP group showed an increase in comparison to preoperative requirements. In the OFA-plus group, 26.1% of patients (n = 6) were discharged without opioid prescription vs. 10.5% in the OP group.
The pain management in these patients is very complex, and it is extremely difficult not to use opioids after surgery. Although the results of our study showed a reduction in opioid requirements at the time of hospital discharge in the group with OFA-plus group, the limited number of cases studied does not allow us to give a definitive conclusion on the matter. The majority of patients who were discharged without opioid prescription had preoperative medical prescription with no opioids or weak opioids. That fact strongly suggests that opioid-induced hyperalgesia and opioid tolerance are important mechanisms that lead to the persistence of severe pain in these patients (4,5,23).
A high percentage of the patients undergoing CCF with EDS-HT/JHS suffer from functional gastrointestinal disturbances with tendency to develop intestinal ileus, nausea and vomiting. Also, they frequently have altered sleep architecture, mood changes, depression and emotional and cognitive disturbances. Preoperative depression or anxiety have been associated with a greater likelihood of adverse outcomes and increased opioid consumption in patients undergoing cervical spine surgery. Our results showed a significant decrease in nausea and vomiting and reduction in the use of anxiolytics in the OFA-plus group (1,3,24).
It seems evident that the lower exposure to opioids in the OFA-plus group contributed to a better postoperative evolution of gastrointestinal function. However, the incidence of constipation was similar in both groups, therefore the preventive use of medication to improve the quality of faeces is important. These patients remain in bed for a long time, have little mobility, a deterioration in physical condition and fluid intake is generally low.
On the other hand, the reduction in the use of anxiolytics in the OFA-plus group may be the result of low-doses of ketamine on mood, the anxiolytic effect of dexmedetomidine, and a better postoperative pain control. Almost all patients studied were young women. The effects of low-dose ketamine as an anti-depressant have been described to be better in young women and adolescent females, as well as producing lower incidence of adverse psychomimetic effects (hallucinations, anxiety or panic attacks) compared to men. In our series, 17.4% (n = 4, one man) of patients had visual hallucinations that justified the temporary suspension of ketamine and the subsequent dose reduction. Haloperidol was administered to two patients, improving symptoms (25).
Another limitation of our study was to evaluate the VAS only at rest. Most of these patients began to sit after 6 postoperative days, and get up or walk after a week, therefore, the VAS score during movement was not considered within our goals.
Mast cell activation syndrome (MCAS) and autonomic symptoms like postural orthostatic tachycardia syndrome (POTS) are frequently present in the patients with EDS-HT/JHS (26).
Some opioids can be MCAS triggers or provoke hemodynamic disturbances due to histamine release. Moreover, many patients with EDS-HT/JHS and MCAS have a medical history of allergy to certain opioids. A thorough preoperative anamnesis should always be done to avoid using triggers (27). Due to the aforementioned, it seems that reducing the use of opioids in these patients is reasonable. Although opioids were used in both groups throughout the hospital stay, there were no events associated with MCAS (28).
In conclusion, it is feasible to administer OFA to patients undergoing CCF with EDS-HT/JHS. Intraoperative plus postoperative use of lidocaine, ketamine, and dexmedetomidine infusions offer better postoperative pain control compared to opioid-based anesthetic/analgesic techniques. The anti-inflammatory and anti-hyperalgesic effects of lidocaine, ketamine, and dexmedetomidine may provide a beneficial effect as part of a more robust multimodal analgesia protocol focused on the management of hyperalgesia and Central Sensitization phenomena.
Although there was no evidence of a reduction in opioid use during the first postoperative week, in the OFA-plus group a lower percentage of patients required methadone throughout the hospitalization period. Moreover, OFA-plus group showed a significant reduction in VAS score compared to OP group throughout hospitalization and discharge. Furthermore, in this group there was a tendency to reduce opioid requirements at the time of hospital discharge compared to preoperative use. Unfortunately, our study did not include a long-term outcome of the patients, another aspect that limits our conclusions about the possible benefits of reducing the perioperative use of opioids in this context.
Certain doubts arise from the present study. First, what would the optimal time to maintain postoperative infusions of lidocaine, ketamine and dexmedetomidine be?. Second, what oral medications could replace the effects of these infusions after one week of the postoperative period?. For example, it could be lamotrigine, carbamazepine, memantine, ketamine, or maybe clonidine. Thirdly, could sufentanil be replaced by some other type of non-opioid analgesic rescue (i.e, medical cannabinoids)?. It is probable that many other questions will arise.