In some patients with extremity osteosarcoma and bone metastases, MEBTP has been widely recognized as the most difficult to treat by conventional medical management, including oral or transmucosal opioids [23, 24]. Intrathecal drug infusion therapy is an effective treatment selection for refractory cancer pain; however, the general consensus on its effectiveness for movement evoked BTP has not yet been reached [16, 25]. The purpose of this study was to investigate the efficacy of ITA with PCIA in the treatment of MEBTP of lower extremity tumors.
High cost limited the use of the implanted intrathecal morphine pump despite it is more suitable for long-term use. Recently, intrathecal morphine infusion therapy via a percutaneous port (IMITPP) has become a popular option for refractory cancer pain in some countries for its relatively lower cost [19]. In the present study, we assessed the efficacy and safety of IMITPP.
Direct analgesic delivery to the neural axis offers immediate access to receptors, bypasses the blood-brain barrier, and minimizes systemic drug interactions. A commonly used mixture for the treatment of intractable pain consists of morphine and bupivacaine. Nevertheless, IT bupivacaine also provides better analgesia in patients with neuropathic pain than in patients with nociceptive pain [22].
In their randomized controlled study, Bäckryd et al [25] evaluated an intrathecal drug delivery system versus comprehensive medical management to treat advanced cancer pain, reporting significant improvement in spontaneous resting pain intensity (SRPI). Nonetheless, MEBTP was not adequately controlled despite ITA. However, besides providing support that ITA is a valuable analgesic technique in spontaneous resting pain intensity (SRPI), our results also revealed that movement-evoked BTP could be adequately controlled in patients with lower extremity osteosarcoma and bone metastases. Since the main purpose of this study was to explore movement-evoked BTP, we chose the lower extremity pain with the greatest impact of movement-evoked BTP. Our results revealed that movement-evoked pain intensity significantly decreased after one month of treatment. The proportions of the drugs in the study have been approved. Still, differences in concentration and dose and the rate of administration could be the most important reason for the diametrically different results of the two studies. In the Bäckryd study [25], their initial dose of intrathecal morphine was adjusted according to pre-ITA doses using an oral-to-intrathecal ratio of 200:1. In the present study, we used the 300:1 ratio, which is in line with the PACC clinical recommendation [26]. Our intrathecal basal starting dose was less than or equal to their study. However, as they used a fully implantable PUMP with just 40 mL in volume, this limited the concentration and volume variation. The maximum capacity of the external PUMP we used was 250ml, allowing us to configure the drug concentration flexibly. In their study, by a combination of morphine (0.2 mg/ mL), bupivacaine (1 mg/ ml) was infused intrathecally. The usual starting rate was 0.5 ml/h with patient-controlled boluses of 0.2 mL available up to twice per hour as needed. In our study, the concentration of morphine (0.1-0.8mg/ mL), bupivacaine (1 mg/ mL), and the dose of bolus were usually set to be consistent with the continuous infusion dose for one hour. The maximum speed was given to 2ml/h, which means that the maximum single bolus dose was 2ml. The lockout period was 10-15 minutes, so our single dose of bolus and the number of bolus were much higher than theirs, but the total dose we used was still within the safe range. At the same time, we customized the treatment for every patient and we always advised them to press the bolus button usually 5-10 minutes before their movement according to their pain intensity. Patient-controlled intrathecal analgesia offered the patient the ability to deliver a bolus of an opioid and local anesthetic to the neuraxis and produce rapid-onset analgesia.
Bäckryd et al. [25] suggested that metastatic bone pain was precisely movement that evoked BTP. The pathophysiology of metastatic bone pain was a complicated matter, but on a basic level, it was reasonable to assume that weight-bearing and movement increase the nociceptive input into the spinal cord. Furthermore, this increase in nociceptive input could occur, especially if there were incipient or actual pathologic fractures or substantial cancer growth into adjacent neural structures. Thus, it seemed that advanced breast or lung cancer with concomitant neuropathic pain was a risk factor for intractable MEBTP despite otherwise successful ITA.
All patients enrolled in our study were patients with lower limb tumors. More interestingly, in all the cancer pain patients we treated with intrathecal analgesia, lower extremity pain was more significantly relieved compared to patients with visceral neuralgia. For these patients, we placed the catheter in T12 due to the fact that spinal neuralgia was involved in more patients with lower limb pain, and sympathetic nerves and splanchnic autonomic nerves were less likely to be involved, which needs to be addressed by future studies.
In addition to the dose, we noticed that another critical factor for the treatment of MEBTP was the time of onset. Patients involved in this study were patients with lower limb tumors, most of whom had poor healing or infection of incision as they mostly underwent surgery, radiation, and chemotherapy, and targeted therapy. Meanwhile, most of the primary tumors or operative incisions were located in the lumbosacral portion or lower extremities. It was very important for these patients to regularly change position to reduce the incision site pressure, pressure sores, and so on. However, the most contradictory thing was the fear of patients due to the active MEBTP, and such patients were unwilling to simply move and change the position, which eventually led to the occurrence of serious complications such as incision rupture and necrosis, pressure sores, lung infection and so on, and eventually aggravated the development of the disease.
In their randomized controlled study, Brogan et al evaluated an intrathecal drug delivery system versus comprehensive medical management in the treatment of advanced cancer pain and compared it with conventional BTP analgesics, revealing PCIA to be associated with a 3-fold faster onset of action, improved efficacy, and high patient satisfaction [16]. We support their findings. In our study, we found that the onset time of ITA-controlled MEBTP was significantly shorter (from 38min to about 8min; p<0.05). ITA dosages were subsequently adjusted according to clinical response but were not prospectively registered. In our daily clinical procedure, patients were instructed to use the bolus function for predictable movement-evoked pain, and the MEBTP could be well controlled. After doing that, we encouraged patients to take the initiative to change their position, thus further reducing the incidence of pressure sores and other complications. Our study revealed encouraging results, considering the active position change was significantly more frequent than in the past. In addition, the use of non-ITA opioids significantly decreased, and the intrathecal use of opioids significantly increased over time. These conclusions were consistent with those of previous studies.
Several studies have shown that intrathecal morphine infusion therapy reduces the incidence of the adverse advents caused by systemic opioids due to high morphine concentrations at the site of action. Several operative and drug-related complications may arise after implantation [27, 28]. Nausea and vomiting, constipation, and respiratory depression were the most frequently reported side effects of opioid administration [28]. In our study, there were no significant changes in these effects compared to the preoperative state. As most patients received systemic opioids in this study, some patients suffered from these side effects of opioids, and the fact that we did not observe the relief of these effects after IMIPTT may be due to the shorter observation time. Adverse effects of intrathecal morphine therapy are common during the initial stage of the treatment; however, these effects usually disappear with standard medical management during the first three months. On the other hand, we could see that IMIPTT did not increase the occurrence of these side effects compared with the traditional treatment. The incidence of drug-related side effects with long-term intrathecal morphine therapy decreases with medical management and dose reduction as therapy continues. Urinary retention following intrathecal morphine administration has an estimated incidence between 42% and 80%. Yet, the incidence of urinary retention with long-term intrathecal morphine therapy has been reported to be 3% [18]. In this study, two more patients had urinary retention compared to preoperative conditions and were managed by temporary urinary catheterization, which was in accordance with the studies above. Two patients experienced a headache from a cerebrospinal fluid leak after a post-arachnoid puncture, which was relieved by conservative treatments. These two patients were unable to remain in the supine position but in the semi-decubitus position even after the operation, which may be the important cause of postoperative headache. These symptoms quickly disappeared with fluid rehydration [29].
Inevitably, there are still some limitations in our study. First, only 12 patients were retrospectively evaluated. An effective analysis of intrathecal opioid efficacy was not possible because the power of such a small sample size was low. Second, it is a retrospective study without long-term follow-ups, which makes it difficult to assess the long-term complications of IMITPP. Therefore, it was not clear whether opioid-induced side effects were reduced following intrathecal therapy. Third, we only could use the NRS scoring system to assess pain without including a scale questionnaire and satisfaction survey according to the medical records in a retrospective study, which prevented us from fully evaluating the comprehensive situation of pain improvement. Therefore, we are currently collecting data in a prospective manner, including various quality of life metrics and breakthrough pain measurements to further investigate whether IMITPP with PCIA is superior for the management of refractory cancer pain and MEBTP.